Boosting ATM activity alleviates ageing and extends lifespan in a mouse model of progeria.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA430333 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6496530_1.fastq.gz | Fastqsanger.gz | |||
| SRR6496530_2.fastq.gz | Fastqsanger.gz | |||
| SRR6496531_1.fastq.gz | Fastqsanger.gz | |||
| SRR6496531_2.fastq.gz | Fastqsanger.gz | |||
| SRR6496532_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 18 |
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Project description:DNA damage accumulates with age (Lombard et al., 2005). However, whether and how robust DNA repair machinery promotes longevity is elusive. Here, we demonstrate that ATM-centered DNA damage response (DDR) progressively declines with senescence and age, while low dose of chloroquine (CQ) activates ATM, promotes DNA damage clearance, rescues age-related metabolic shift, and prolongs replicative lifespan. Molecularly, ATM phosphorylates SIRT6 deacetylase and thus prevents MDM2-mediated ubiquitination and proteasomal degradation. Extra copies of Sirt6 extend lifespan in Atm-/- mice, with restored metabolic homeostasis. Moreover, the treatment with CQ remarkably extends lifespan of Caenorhabditis elegans, but not the ATM-1 mutants. In a progeria mouse model with low DNA repair capacity, long-term administration of CQ ameliorates premature aging features and extends lifespan. Thus, our data highlights a pro-longevity role of ATM, for the first time establishing direct causal links between robust DNA repair machinery and longevity, and providing therapeutic strategy for progeria and age-related metabolic diseases.
| S-EPMC5957528 | biostudies-literature
Project description:Transcriptional profiling of human control and Néstor-Guillermo Progeria Syndrome (NGPS) fibroblasts and induced pluripotent stem cells (iPSCs). Somatic cell reprogramming involves rejuvenation of adult cells and relies on the ability to erase age-associated molecular marks. Accordingly, reprogramming efficiency declines with ageing, and age-associated features such as genetic instability, cell senescence or telomere shortening negatively affect this process. However, the regulatory mechanisms that constitute age-associated barriers for cell reprogramming remain largely unknown. Here, by using cells from patients with premature ageing, we demonstrate that NF-κB activation is a critical barrier for the generation of induced pluripotent stem cells (iPSCs) in ageing. We show that NF-κB repression occurs during cell reprogramming towards a pluripotent state. Conversely, ageing-associated NF-κB hyperactivation impairs generation of iPSCs by eliciting reprogramming repressors DOT1L and YY1, reinforcing cell senescence signals and down-regulating pluripotency genes. We also show that genetic and pharmacological NF-κB inhibitory strategies significantly increase the reprogramming efficiency of fibroblasts from Néstor-Guillermo Progeria Syndrome (NGPS) and Hutchinson-Gilford Progeria Syndrome (HGPS) patients, as well as from normal aged donors. Finally, we demonstrate that DOT1L inhibition in vivo ameliorates the accelerated ageing phenotype and extends lifespan in a progeroid animal model. Collectively, our results provide evidence for a novel role of NF-κB in the control of cell fate transitions and reinforce the interest of studying age-associated molecular impairments to implement cell reprogramming methodologies, and to identify new targets of rejuvenation strategies. Control and NGPS fibroblasts were reprogrammed. RNA was extracted and transcriptional profiling was obtained with GeneChip Human Exon 1.0 ST Arrays.
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Project description:Transcriptional profiling of human control and Néstor-Guillermo Progeria Syndrome (NGPS) mesenchymal stem cells (MSCs). Somatic cell reprogramming involves rejuvenation of adult cells and relies on the ability to erase age-associated molecular marks. Accordingly, reprogramming efficiency declines with ageing, and age-associated features such as genetic instability, cell senescence or telomere shortening negatively affect this process. However, the regulatory mechanisms that constitute age-associated barriers for cell reprogramming remain largely unknown. Here, by using cells from patients with premature ageing, we demonstrate that NF-κB activation is a critical barrier for the generation of induced pluripotent stem cells (iPSCs) in ageing. We show that NF-κB repression occurs during cell reprogramming towards a pluripotent state. Conversely, ageing-associated NF-κB hyperactivation impairs generation of iPSCs by eliciting reprogramming repressors DOT1L and YY1, reinforcing cell senescence signals and down-regulating pluripotency genes. We also show that genetic and pharmacological NF-κB inhibitory strategies significantly increase the reprogramming efficiency of fibroblasts from Néstor-Guillermo Progeria Syndrome (NGPS) and Hutchinson-Gilford Progeria Syndrome (HGPS) patients, as well as from normal aged donors. Finally, we demonstrate that DOT1L inhibition in vivo ameliorates the accelerated ageing phenotype and extends lifespan in a progeroid animal model. Collectively, our results provide evidence for a novel role of NF-κB in the control of cell fate transitions and reinforce the interest of studying age-associated molecular impairments to implement cell reprogramming methodologies, and to identify new targets of rejuvenation strategies. Control and NGPS MSCs were differentiated into bone in the presence or absence of sodium salicylate. Total RNA was extracted and global gene expression was analyzed.
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