A mild increase in nutrient signaling to mTORC1 in mice leads to parenchymal damage, myeloid inflammation and shortened lifespan.

Autor: Ortega-Molina A; Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. aortega@cbm.csic.es.; Metabolism in cancer and aging Laboratory, Immune System Development And Function Department, Centro de Biología Molecular Severo Ochoa (CBM), Madrid, Spain. aortega@cbm.csic.es., Lebrero-Fernández C; Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Metabolism in cancer and aging Laboratory, Immune System Development And Function Department, Centro de Biología Molecular Severo Ochoa (CBM), Madrid, Spain., Sanz A; Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Madrid, Spain., Calvo-Rubio M; Translational Gerontology Branch, National Institute on Aging (NIA), National Institutes of Health (NIH), Baltimore, MD, USA., Deleyto-Seldas N; Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Madrid, Spain., de Prado-Rivas L; Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Madrid, Spain., Plata-Gómez AB; Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Madrid, Spain., Fernández-Florido E; Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Madrid, Spain., González-García P; Histopathology Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain., Vivas-García Y; Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Madrid, Spain., Sánchez García E; Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Madrid, Spain., Graña-Castro O; Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Institute of Applied Molecular Medicine (IMMA-Nemesio Díez), Department of Basic Medical Sciences, School of Medicine, San Pablo-CEU University, CEU Universities, Boadilla del Monte, Madrid, Spain., Price NL; Translational Gerontology Branch, National Institute on Aging (NIA), National Institutes of Health (NIH), Baltimore, MD, USA., Aroca-Crevillén A; Cardiovascular Regeneration Program, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain., Caleiras E; Histopathology Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain., Monleón D; Department of Pathology, University of Valencia, Valencia, Spain; Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), Institute of Health Research-INCLIVA, Valencia, Spain., Borrás C; Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), MiniAging Research Group, Institute of Health Research-INCLIVA, Valencia, Spain., Casanova-Acebes M; Cancer Immunity Laboratory, Spanish National Cancer Research Centre (CNIO), Madrid, Spain., de Cabo R; Translational Gerontology Branch, National Institute on Aging (NIA), National Institutes of Health (NIH), Baltimore, MD, USA., Efeyan A; Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. aefeyan@cnio.es.
Jazyk: angličtina
Zdroj: Nature aging [Nat Aging] 2024 Aug; Vol. 4 (8), pp. 1102-1120. Date of Electronic Publication: 2024 Jun 07.
DOI: 10.1038/s43587-024-00635-x
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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