Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Parenchymal damage and myeloid inflammation link the Rag GTPase – mTORC1 axis to mammalian aging [young]

ABSTRACT: The mechanistic target of rapamycin complex 1 (mTORC1) controls cellular anabolism in response to nutrient sufficiency and growth factor signaling, and genetic and pharmacological inhibition of mTORC1 extends longevity across eukaryotes. Up to date, mouse models to analyze the mechanisms of aging governed by mTORC1 has been limited by detrimental pleiotropic consequences of genetically-increased mTORC1 activity in mice. RragcS74N/+, RragcS74C/+ and RragcT89N/+ knock-in mice endogenously express active mutant variants of RagC, a GTPase that signaling nutrient sufficiency to mTORC1. Rragcmutant/+ mice show an only moderate increase in nutrient signaling to mTORC1, and after one year of life exhibit multiple features of a premature aging phenotype that include prominent senescence in peripheral organs, parenchymal expression of inflammatory and chemo-attractant molecules, increased myeloid inflammation and extensive features of inflammaging. In vivo transplantation and ex vivo functional experiments with bone marrow-derived cells show that myeloid cells are abnormally activated by parenchymal signals evoked from Rragcmut/+ organs, to where myeloid cells extravasate to inflict additional inflammatory damage. Therapeutic suppression of myeloid inflammation in old Rragcmut/+ attenuates features of premature aging and extends longevity. We provide the first genetic link of elevated nutrient – mTORC1 activity and premature aging in mammals, and provide support for a two-component model in which increased nutrient signaling drives parenchymal damage and myeloid inflammation precipitates organ deterioration and accelerated aging.

ORGANISM(S): Mus musculus

PROVIDER: GSE221284 | GEO | 2024/04/02

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Parenchymal damage and myeloid inflammation link the Rag GTPase – mTORC1 axis to mammalian aging [old]

Project description:The mechanistic target of rapamycin complex 1 (mTORC1) controls cellular anabolism in response to nutrient sufficiency and growth factor signaling, and genetic and pharmacological inhibition of mTORC1 extends longevity across eukaryotes. Up to date, mouse models to analyze the mechanisms of aging governed by mTORC1 has been limited by detrimental pleiotropic consequences of genetically-increased mTORC1 activity in mice. RragcS74N/+, RragcS74C/+ and RragcT89N/+ knock-in mice endogenously express active mutant variants of RagC, a GTPase that signaling nutrient sufficiency to mTORC1. Rragcmutant/+ mice show an only moderate increase in nutrient signaling to mTORC1, and after one year of life exhibit multiple features of a premature aging phenotype that include prominent senescence in peripheral organs, parenchymal expression of inflammatory and chemo-attractant molecules, increased myeloid inflammation and extensive features of inflammaging. In vivo transplantation and ex vivo functional experiments with bone marrow-derived cells show that myeloid cells are abnormally activated by parenchymal signals evoked from Rragcmut/+ organs, to where myeloid cells extravasate to inflict additional inflammatory damage. Therapeutic suppression of myeloid inflammation in old Rragcmut/+ attenuates features of premature aging and extends longevity. We provide the first genetic link of elevated nutrient – mTORC1 activity and premature aging in mammals, and provide support for a two-component model in which increased nutrient signaling drives parenchymal damage and myeloid inflammation precipitates organ deterioration and accelerated aging.

2024-04-02 | GSE221283 | GEO

Parenchymal damage and myeloid inflammation link the Rag GTPase – mTORC1 axis to mammalian aging [liver]

2024-04-02 | GSE221286 | GEO

Parenchymal damage and myeloid inflammation link the Rag GTPase – mTORC1 axis to mammalian aging [neutrophils]

2024-04-02 | GSE221285 | GEO

Neuronal mTORC1 inhibition promotes longevity without suppressing anabolic growth and reproduction in C. elegans

Project description:mTORC1 (mechanistic target of rapamycin complex 1) is a metabolic sensor that promotes growth when nutrients are abundant. Ubiquitous inhibition of mTORC1 extends lifespan in multiple organisms but also disrupts several anabolic processes resulting in stunted growth, slowed development, reduced fertility, and disrupted metabolism. However, it is unclear if these pleotropic effects of mTORC1 inhibition can be uncoupled from longevity. Here, we utilize the auxin-inducible degradation (AID) system to restrict mTORC1 inhibition to C. elegans neurons. We find that neuron-specific degradation of RAGA-1, an upstream activator of mTORC1, or LET-363, the ortholog of mammalian mTOR, is sufficient to extend lifespan in C. elegans. Unlike raga-1 loss of function genetic mutations or somatic AID of RAGA-1, neuronal AID of RAGA-1 robustly extends lifespan without impairing body size, developmental rate, brood size or neuronal function. Moreover, while somatic degradation of RAGA-1 alters the expression of thousands of genes, demonstrating the widespread effects of mTORC1 inhibition, neuronal degradation of RAGA-1 only results in around 200 differentially expressed genes with a specific enrichment in metabolism and stress response. Notably, our work demonstrates that targeting mTORC1 specifically in the nervous system in C. elegans uncouples longevity from growth and reproductive impairments, and that many canonical effects of low mTORC1 activity are not required to promote healthy aging. These data challenge previously held ideas about the mechanisms of mTORC1 lifespan extension and underscore the potential of promoting longevity by neuron-specific mTORC1 modulation.

2023-07-18 | GSE237060 | GEO

Parenchymal damage and myeloid inflammation link the Rag GTPase – mTORC1 axis to mammalian aging

Project description:Parenchymal damage and myeloid inflammation link the Rag GTPase – mTORC1 axis to mammalian aging

| PRJNA913829 | ENA

Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes molecularly distinct from physiologic stem cell aging

Project description:Somatic stem cells mediate tissue maintenance for the lifetime of an organism. Despite the well-established longevity that is a prerequisite for such function, accumulating data argue for compromised stem cell function with age. Identifying the mechanisms underlying age-dependent stem cell dysfunction is therefore key to understand the aging process. Using a model that carries a proofreading defective mitochondrial DNA polymerase, we demonstrate hematopoietic defects reminiscent of premature HSC aging including anemia, lymphopenia and myeloid lineage skewing. However, in contrast to physiologic stem cell aging, rapidly accumulating mitochondrial DNA mutations displayed little involvement of the hematopoietic stem cell pool but rather with distinct differentiation blocks and/or disappearance of downstream progenitors. Hematopoietic stem cells (HSC) has been sorted out from midaged wildtype and mutator mice and compared with stem cells sorted from young and and old wt mice

2011-05-06 | E-GEOD-27686 | biostudies-arrayexpress

Parenchymal damage and myeloid inflammation link the Rag GTPase – mTORC1 axis to mammalian aging [old]

Project description:Parenchymal damage and myeloid inflammation link the Rag GTPase – mTORC1 axis to mammalian aging [old]

| PRJNA913833 | ENA

Parenchymal damage and myeloid inflammation link the Rag GTPase – mTORC1 axis to mammalian aging [young]

Project description:Parenchymal damage and myeloid inflammation link the Rag GTPase – mTORC1 axis to mammalian aging [young]

| PRJNA913832 | ENA

Parenchymal damage and myeloid inflammation link the Rag GTPase – mTORC1 axis to mammalian aging [neutrophils]

Project description:Parenchymal damage and myeloid inflammation link the Rag GTPase – mTORC1 axis to mammalian aging [neutrophils]

| PRJNA913835 | ENA

Parenchymal damage and myeloid inflammation link the Rag GTPase – mTORC1 axis to mammalian aging [liver]

Project description:Parenchymal damage and myeloid inflammation link the Rag GTPase – mTORC1 axis to mammalian aging [liver]