Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/20206
Título
A mild increase in nutrient signaling to mTORC1 in mice leads to parenchymal damage, myeloid inflammation and shortened lifespan.
Autor(es)
Ortega-Molina, Ana CNIO | Lebrero-Fernández, Cristina | Sanz, Alba | Calvo-Rubio, Miguel | Deleyto-Seldas, Nerea | de Prado-Rivas, Lucía | Plata-Gómez, Ana Belén | Fernández-Florido, Elena | González-García, Patricia | Vivas-García, Yurena | Sánchez García, Elena | Graña-Castro, Osvaldo CNIO | Price, Nathan L | Aroca-Crevillén, Alejandra | Caleiras, Eduardo | Monleón, Daniel | Borrás, Consuelo | Casanova-Acebes, María | de Cabo, Rafael | Efeyan, Alejo CNIO
Fecha de publicación
2024-06-07
Cita
Nat Aging. 2024 Jun 7.
Idioma
Inglés
Tipo de documento
journal article
Resumen
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.
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