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Tetracyclines are clinically used antibiotics long observed to exert beneficial effects in age\u2010associated diseases and extend lifespan in model organisms, though the underlying mechanisms remain unclear. Here, we systematically profiled commercially available tetracyclines and show that translation attenuation is a general property of the tetracycline class. Importantly, we identify the atypical tetracyclines 4\u2010epiminocycline and 12\u2010aminominocycline, which attenuate translation independently of antibiotic activity and integrated stress response (ISR) activation. These compounds extend lifespan in\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>C. elegans<\/jats:italic>\n                    <\/jats:styled-content>\n                    , attenuate translation in human induced neurons, reduce hippocampal protein synthesis in\u00a0vivo, and protect neurons from ferroptotic stress. Together, our results demonstrate that pharmacological attenuation of translation is sufficient to promote longevity and establish translation attenuation as a druggable longevity mechanism in mammals.\n                  <\/jats:p>","DOI":"10.1111\/acel.70587","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T17:02:56Z","timestamp":1781802176000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Atypical Tetracyclines Promote Longevity and Ferroptotic Neuroprotection via Translation Attenuation"],"prefix":"10.1111","volume":"25","author":[{"given":"Khalyd J.","family":"Clay","sequence":"first","affiliation":[{"name":"Department of Molecular and Cellular Biology The Scripps Research Institute  La Jolla California USA"},{"name":"Department of Neuroscience The Scripps Research Institute  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8164-8452","authenticated-orcid":false,"given":"Manuel","family":"Sanchez\u2010Alavez","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology The Scripps Research Institute  La Jolla California USA"},{"name":"Department of Neuroscience The Scripps Research Institute  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Newman","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology The Scripps Research Institute  La Jolla California USA"},{"name":"Department of Neuroscience The Scripps Research Institute  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Na","sequence":"additional","affiliation":[{"name":"Department of Neuroscience The Scripps Research Institute  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana P. 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