A mild increase in nutrient signaling to mTORC1 in mice leads to parenchymal damage, myeloid inflammation and shortened lifespan Article Swipe
Ana Ortega-Molina
,
Cristina Lebrero‐Fernández
,
Alba Sanz
,
Miguel Calvo‐Rubio
,
Nerea Deleyto-Seldas
,
Lucía de Prado-Rivas
,
Ana Belén Plata-Gómez
,
Elena Fernández-Florido
,
Patricia González‐García
,
Yurena Vivas
,
Elena García
,
Osvaldo Graña‐Castro
,
Nathan L. Price
,
Alejandra Aroca-Crevillén
,
Eduardo Caleiras
,
Daniel Monleón
,
Consuelo Borrás
,
María Casanova-Acebes
,
Rafael de Cabo
,
Alejo Efeyan
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1038/s43587-024-00635-x
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1038/s43587-024-00635-x
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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- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1038/s43587-024-00635-x
- https://www.nature.com/articles/s43587-024-00635-x.pdf
- OA Status
- hybrid
- Cited By
- 26
- References
- 90
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4399437494
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Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W4399437494Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1038/s43587-024-00635-xDigital Object Identifier
- Title
-
A mild increase in nutrient signaling to mTORC1 in mice leads to parenchymal damage, myeloid inflammation and shortened lifespanWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2024Year of publication
- Publication date
-
2024-06-07Full publication date if available
- Authors
-
Ana Ortega-Molina, Cristina Lebrero‐Fernández, Alba Sanz, Miguel Calvo‐Rubio, Nerea Deleyto-Seldas, Lucía de Prado-Rivas, Ana Belén Plata-Gómez, Elena Fernández-Florido, Patricia González‐García, Yurena Vivas, Elena García, Osvaldo Graña‐Castro, Nathan L. Price, Alejandra Aroca-Crevillén, Eduardo Caleiras, Daniel Monleón, Consuelo Borrás, María Casanova-Acebes, Rafael de Cabo, Alejo EfeyanList of authors in order
- Landing page
-
https://doi.org/10.1038/s43587-024-00635-xPublisher landing page
- PDF URL
-
https://www.nature.com/articles/s43587-024-00635-x.pdfDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
hybridOpen access status per OpenAlex
- OA URL
-
https://www.nature.com/articles/s43587-024-00635-x.pdfDirect OA link when available
- Concepts
-
Inflammation, Myeloid, mTORC1, Biology, Cell biology, Parenchyma, Myelopoiesis, Bone marrow, Longevity, Signal transduction, Cancer research, PI3K/AKT/mTOR pathway, Immunology, Haematopoiesis, Stem cell, Genetics, BotanyTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
26Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 21, 2024: 4, 2013: 1Per-year citation counts (last 5 years)
- References (count)
-
90Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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