2026-05-08T20:04:31Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/202062024-09-27T08:48:13Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Ortega-Molina, Ana author Lebrero-Fernández, Cristina author Sanz, Alba author Calvo-Rubio, Miguel author Deleyto-Seldas, Nerea author de Prado-Rivas, Lucía author Plata-Gómez, Ana Belén author Fernández-Florido, Elena author González-García, Patricia author Vivas-García, Yurena author Sánchez García, Elena author Graña-Castro, Osvaldo author Price, Nathan L author Aroca-Crevillén, Alejandra author Caleiras, Eduardo author Monleón, Daniel author Borrás, Consuelo author Casanova-Acebes, María author de Cabo, Rafael author Efeyan, Alejo author 2024-06-07 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. Nat Aging. 2024 Jun 7. 10.1038/s43587-024-00635-x 2662-8465 Nature aging 38849535 http://hdl.handle.net/20.500.12105/20206 A mild increase in nutrient signaling to mTORC1 in mice leads to parenchymal damage, myeloid inflammation and shortened lifespan.