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Many drugs have targets in the network because of its roles in cancer and metabolic disease and are candidates for repurposing as geroprotectors. Rapamycin, an established geroprotective drug, blocks mTORC1 signaling, and trametinib inhibits the Ras\u2013MEK\u2013ERK pathway. In this study, we assessed survival and health of male and female mice treated with trametinib, rapamycin or their combination. We show here that trametinib treatment extended lifespan in both sexes and that its combination with rapamycin was additive. Combination treatment reduced liver tumors in both sexes and spleen tumors in male mice, blocked the age-related increase in brain glucose uptake and strongly reduced inflammation in brain, kidney, spleen and muscle and circulating levels of pro-inflammatory cytokines. We conclude that trametinib is a geroprotector in mice and that its combination with rapamycin is more effective than either drug alone, making the combination a candidate for repurposing as a gerotherapy in humans.<\/jats:p>","DOI":"10.1038\/s43587-025-00876-4","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T05:02:14Z","timestamp":1748408534000},"page":"1249-1265","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["The geroprotectors trametinib and rapamycin combine additively to extend mouse healthspan and lifespan"],"prefix":"10.1038","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-1853-0308","authenticated-orcid":false,"given":"Lisonia","family":"Gkioni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Nespital","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3518-7074","authenticated-orcid":false,"given":"Maarouf","family":"Baghdadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5043-8145","authenticated-orcid":false,"given":"Carolina","family":"Monz\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jitin","family":"Bali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taim","family":"Nassr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Lena","family":"Cremer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3891-2123","authenticated-orcid":false,"given":"Andreas","family":"Beyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4483-3701","authenticated-orcid":false,"given":"Joris","family":"Deelen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heiko","family":"Backes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1539-5346","authenticated-orcid":false,"given":"Sebastian","family":"Gr\u00f6nke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Partridge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,28]]},"reference":[{"key":"876_CR1","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1038\/s41580-019-0199-y","volume":"21","author":"GY Liu","year":"2020","unstructured":"Liu, G. 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