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 |