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dc.contributor.author | Ortega-Molina, Ana | |
dc.contributor.author | Lebrero-Fernández, Cristina | |
dc.contributor.author | Sanz, Alba | |
dc.contributor.author | Calvo-Rubio, Miguel | |
dc.contributor.author | Deleyto-Seldas, Nerea | |
dc.contributor.author | de Prado-Rivas, Lucía | |
dc.contributor.author | Plata-Gómez, Ana Belén | |
dc.contributor.author | Fernández-Florido, Elena | |
dc.contributor.author | González-García, Patricia | |
dc.contributor.author | Vivas-García, Yurena | |
dc.contributor.author | Sánchez García, Elena | |
dc.contributor.author | Graña-Castro, Osvaldo | |
dc.contributor.author | Price, Nathan L | |
dc.contributor.author | Aroca-Crevillén, Alejandra | |
dc.contributor.author | Caleiras, Eduardo | |
dc.contributor.author | Monleón, Daniel | |
dc.contributor.author | Borrás, Consuelo | |
dc.contributor.author | Casanova-Acebes, María | |
dc.contributor.author | de Cabo, Rafael | |
dc.contributor.author | Efeyan, Alejo | |
dc.date.accessioned | 2024-07-08T12:40:27Z | |
dc.date.available | 2024-07-08T12:40:27Z | |
dc.date.issued | 2024-06-07 | |
dc.identifier.citation | Nat Aging. 2024 Jun 7. | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/20206 | |
dc.description.abstract | The mechanistic target of rapamycin complex 1 controls cellular anabolism in response to growth factor signaling and to nutrient sufficiency signaled through the Rag GTPases. Inhibition of mTOR reproducibly extends longevity across eukaryotes. Here we report that mice that endogenously express active mutant variants of RagC exhibit multiple features of parenchymal damage that include senescence, expression of inflammatory molecules, increased myeloid inflammation with extensive features of inflammaging and a ~30% reduction in lifespan. Through bone marrow transplantation experiments, we show that myeloid cells are abnormally activated by signals emanating from dysfunctional RagC-mutant parenchyma, causing neutrophil extravasation that inflicts additional inflammatory damage. Therapeutic suppression of myeloid inflammation in aged RagC-mutant mice attenuates parenchymal damage and extends survival. Together, our findings link mildly increased nutrient signaling to limited lifespan in mammals, and support a two-component process of parenchymal damage and myeloid inflammation that together precipitate a time-dependent organ deterioration that limits longevity. | es_ES |
dc.description.sponsorship | We thank D.M. Sabatini, R. Jaenisch, S. Markoulaki and the Whitehead Institute for Biomedical Research CRISPR facility for zygote injections, the CNIO Flow Cytometry, Histopathology, Animal Facility and Genomics Core Units, the Computational Biology and Genomic Core at the NIA and the Advanced Light Microscopy Facility at the CBM for technical support. We also thank D. Sancho for providing fluorescent E.coli and A. Hidalgo for help with the analysis of the impact of myeloid cells. Research was supported by the RETOS projects Programme of Spanish Ministry of Science, Innovation and Universities, Spanish State Research Agency, co-funded by the European Regional Development Fund (grants PID2019-104012RB-I00 and PID2022-136413OB-I00), EU-H2020 Programme (ERC-2014-STG-638891), a Ramon y Cajal Award from MICIU/AEI (RYC-2013-13546), Spanish Association Against Cancer Research Scientific Foundation Laboratory Grant (LABAE16001EFEY/ AECC) Beca de Investigación en Oncología Olivia Roddom, FERO Grant for Research in Oncology and La Caixa Banking Foundation (LCF/PR/HR21/0046). Miguel Servet Fellowship and grant award (MS16/00112 and CP16/00112) and project PI18/00816 within the Health Strategic Action from the ISCIII (to A.O.-M.), both co-funded by the European Regional Development Fund. A.O.M. is a recipient of a Ramon y Cajal Award from MICINN/AEI (RYC-2019-027280-I). This research was supported in part by the Intramural Research Program at the NIA, National Institutes of Health. C.L.F. is supported by a PIE-CSIC (20212AT020) grant. Y.V.G. is a beneficiary of a CNIO Friends contract funded by the Domingo Martinez Foundation. C.B. and D.M. acknowledge grant PID2020-113839RB-I00 funded by MCIN/AEI/10.13039/501100011033 and grant PID2019-108973RB-C22 funded by MCIN/AEI/10.13039/501100011033, respectively. A.B.P.-G., L.d.P.-R., N.D.-S. and E.S.G. are recipients of Ayudas de Contratos Predoctorales para la Formación de Doctores from MICIU/ AEI (BES-2017-081381, PRE-2019-090891, BES-2016-077410 and PRE2020-095127), E.F.F. is a PIPF-2022/SAL-GL-24382 fellow from the Autonomous Community of Madrid and A.A.C. is a fellow from the La Caixa Foundation (ID 100010434 LCF/BQ/DR19/11740022). A.E. is an EMBO Young Investigator. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Nature Publishing Group | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.title | A mild increase in nutrient signaling to mTORC1 in mice leads to parenchymal damage, myeloid inflammation and shortened lifespan. | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Atribución 4.0 Internacional | * |
dc.identifier.pubmedID | 38849535 | es_ES |
dc.identifier.doi | 10.1038/s43587-024-00635-x | es_ES |
dc.contributor.funder | Ministerio de Ciencia, Innovación y Universidades (España) | es_ES |
dc.contributor.funder | Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) | es_ES |
dc.contributor.funder | Asociación Española Contra el Cáncer | es_ES |
dc.contributor.funder | Fundación La Caixa | es_ES |
dc.contributor.funder | Instituto de Salud Carlos III | es_ES |
dc.contributor.funder | Comunidad de Madrid (España) | es_ES |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 2662-8465 | es_ES |
dc.relation.publisherversion | 10.1038/s43587-024-00635-x | es_ES |
dc.identifier.journal | Nature aging | es_ES |
dc.repisalud.orgCNIC | CNIC::Grupos de investigación::Imagen de la Inflamación Cardiovascular y la Respuesta Inmune | es_ES |
dc.repisalud.institucion | CNIC | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/EC/H2020/ERC-2014-STG-638891 | es_ES |
dc.rights.accessRights | open access | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PID2019-104012RB-I00 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PID2022-136413OB-I00 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/RYC-2013-13546 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/LCF/PR/HR21/0046 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/MS16/00112 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/CP16/00112 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PI18/00816 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/RYC-2019-027280-I | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PID2020-113839RB-I00 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/MCIN/AEI/10.13039/501100011033 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PID2019-108973RB-C22 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/BES-2017-081381 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PRE-2019-090891 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/BES-2016-077410 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PRE2020-095127 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PIPF-2022/SAL-GL-24382 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/LCF/BQ/DR19/11740022 | es_ES |