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The mTOR pathway is a central driver of aging-related diseases, such as cancer, chronic inflammation and neurodegeneration; pharmacological inhibition with rapamycin is associated with reduced aged-related morbidity and increased lifespan across species. Nonetheless, concerns remain about the use of rapamycin, a well-established immunosuppressant in transplant medicine, as an anti-aging intervention. Here, we evaluated the impact of prolonged low-dose dietary rapamycin on the aging immune system. Treatment did not significantly alter innate or adaptive immune cell populations, including brain resident microglia; however, it attenuated the age-associated accumulation of IL-17\u2013producing \u03b3\u03b4 T cells, particularly in the peritoneal cavity. After a peripheral inflammatory LPS challenge, circulating IL-17 levels were significantly reduced and correlated with an attenuation of microglia inflammatory phenotype. These findings suggest that prolonged low-dose rapamycin exposure exerts minor systemic immune changes, while selectively limiting age-related \u03b3\u03b4 T cell expansion and neuroinflammation associated with systemic inflammation.<\/jats:p>","DOI":"10.1371\/journal.pone.0343183","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T17:26:30Z","timestamp":1779989190000},"page":"e0343183","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Long-term rapamycin treatment suppresses IL-17-producing gamma delta T cells and blunts neuroinflammation in aging"],"prefix":"10.1371","volume":"21","author":[{"given":"Clement","family":"Torrent","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Gagliardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"F\u00fclle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1680-4199","authenticated-orcid":true,"given":"Ignazio","family":"Antignano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Eugenia","family":"Bernis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Stork","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Bano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8659-9867","authenticated-orcid":true,"given":"Melania","family":"Capasso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lily","family":"Keane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"pone.0343183.ref001","article-title":"Aging: The Biology of Senescence.","volume-title":"Developmental Biology. 6th edition [Internet]","author":"SF Gilbert","year":"2000"},{"issue":"6","key":"pone.0343183.ref002","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The hallmarks of aging","volume":"153","author":"C L\u00f3pez-Ot\u00edn","year":"2013","journal-title":"Cell"},{"key":"pone.0343183.ref003","doi-asserted-by":"crossref","DOI":"10.12688\/f1000research.17196.1","article-title":"mTOR as a central regulator of lifespan and aging","volume":"8","author":"D Papadopoli","year":"2019","journal-title":"F1000Res"},{"issue":"5022","key":"pone.0343183.ref004","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1126\/science.1715094","article-title":"Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast","volume":"253","author":"J Heitman","year":"1991","journal-title":"Science"},{"key":"pone.0343183.ref005","first-page":"362","article-title":"The mTOR pathway in the control of protein synthesis","volume":"21","author":"X Wang","year":"2006","journal-title":"Physiology (Bethesda)"},{"issue":"1","key":"pone.0343183.ref006","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/s41392-023-01608-z","article-title":"Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease","volume":"8","author":"V Panwar","year":"2023","journal-title":"Signal Transduct Target Ther"},{"issue":"8","key":"pone.0343183.ref007","doi-asserted-by":"crossref","first-page":"3272","DOI":"10.1172\/JCI67674","article-title":"Rapamycin extends murine lifespan but has limited effects on aging","volume":"123","author":"F Neff","year":"2013","journal-title":"J Clin Invest"},{"key":"pone.0343183.ref008","doi-asserted-by":"crossref","first-page":"907348","DOI":"10.3389\/fcvm.2022.907348","article-title":"Modulation of mTOR Signaling in Cardiovascular Disease to Target Acute and Chronic Inflammation","volume":"9","author":"M Kaldirim","year":"2022","journal-title":"Front Cardiovasc Med"},{"issue":"3","key":"pone.0343183.ref009","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.cmet.2014.01.001","article-title":"Rapamycin: one drug, many effects","volume":"19","author":"J Li","year":"2014","journal-title":"Cell Metabolism"},{"issue":"10","key":"pone.0343183.ref010","doi-asserted-by":"crossref","first-page":"721","DOI":"10.7164\/antibiotics.28.721","article-title":"Rapamycin (AY-22,989), a new antifungal antibiotic. 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Hurez","year":"2015","journal-title":"Aging Cell"},{"issue":"34","key":"pone.0343183.ref036","article-title":"Murine CD27(-) V\u03b36(+) \u03b3\u03b4 T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages","volume":"111","author":"M Rei","year":"2014","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"pone.0343183.ref037","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1053\/j.gastro.2007.11.056","article-title":"Exacerbating role of gammadelta T cells in chronic colitis of T-cell receptor alpha mutant mice","volume":"134","author":"M Nanno","year":"2008","journal-title":"Gastroenterology"},{"issue":"4","key":"pone.0343183.ref038","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/j.celrep.2012.02.007","article-title":"PI3K-Akt-mTORC1-S6K1\/2 axis controls Th17 differentiation by regulating Gfi1 expression and nuclear translocation of ROR\u03b3","volume":"1","author":"Y Kurebayashi","year":"2012","journal-title":"Cell Rep"},{"issue":"6","key":"pone.0343183.ref039","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1016\/j.immuni.2009.04.014","article-title":"The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment","volume":"30","author":"GM Delgoffe","year":"2009","journal-title":"Immunity"},{"issue":"4","key":"pone.0343183.ref040","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/ni.2005","article-title":"The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2","volume":"12","author":"GM Delgoffe","year":"2011","journal-title":"Nat Immunol"},{"issue":"7701","key":"pone.0343183.ref041","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/s41586-018-0023-4","article-title":"Innate immune memory in the brain shapes neurological disease hallmarks","volume":"556","author":"A-C Wendeln","year":"2018","journal-title":"Nature"},{"key":"pone.0343183.ref042","doi-asserted-by":"crossref","first-page":"108898","DOI":"10.1016\/j.intimp.2022.108898","article-title":"IL-17A drives cognitive aging probably via inducing neuroinflammation and theta oscillation disruption in the hippocampus","volume":"108","author":"Y Li","year":"2022","journal-title":"Int Immunopharmacol"},{"issue":"1","key":"pone.0343183.ref043","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s40659-024-00504-2","article-title":"Increased levels and activation of the IL-17 receptor in microglia contribute to enhanced neuroinflammation in cerebellum of hyperammonemic rats","volume":"57","author":"YM Arenas","year":"2024","journal-title":"Biol Res"},{"issue":"1","key":"pone.0343183.ref044","doi-asserted-by":"crossref","first-page":"6779","DOI":"10.1038\/s41467-025-62181-3","article-title":"Small intestinal \u03b3\u03b4 T17 cells promote SAE through STING\/C1q-induced microglial synaptic 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