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Disentangling mTOR signalling from the lifespan extending effect of dietary restriction in progeroid DNA-repair deficient mice

ABSTRACT: Dietary restriction (DR) and rapamycin, the best-known DR-mimetic, are two intervention that extend health- and lifespan across multiple species. We have recently shown that DR works extremely well in progeroid DNA repair deficient mice and dramatically extend their lifespan by ~200%. We next questioned the applicability of rapamycin in these mouse mutants. Here we show that treatments with rapamycin did significantly lower mTOR-signalling but did not improve the lifespan of DNA repair deficient Ercc1{delta}/- mice. These data are an extended version of the data in GEO Series GSE77321

ORGANISM(S): Mus musculus

PROVIDER: GSE149029 | GEO | 2021/01/25

REPOSITORIES: GEO

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Lifespan extension by diet restriction in DNA repair deficient progeroid Ercc1Δ/- mice [mRNA]

Project description:DNA repair-deficient Ercc1Δ/- mice show premature cell death, senescence and numerous accelerated aging features limiting lifespan to 4-6 month. Simultaneously they exhibit a ‘survival response’, which suppresses growth and enhances maintenance, resembling the anti-aging response induced by dietary restriction (DR). Here we report that subjecting these progeroid, dwarf mutants to actual dietary restriction (DR) resulted in the largest lifespan increase recorded in mammals. Thirty percent DR tripled median and maximal remaining lifespan, and drastically retarded numerous aspects of accelerated aging, e.g. DR animals retained 50% more neurons and maintained full motoric function. The DR response in Ercc1Δ/- mice resembled DR in wild type animals including reduced insulin signaling. Interestingly, ad libitum Ercc1Δ/- liver expression profiles showed preferential extinction of expression of long genes, consistent with genome-wide accumulation of stochastic, transcription-blocking lesions, which affect long genes more than short ones. DR largely prevented this decline of transcriptional output, indicating that DR prolongs genome function. Our findings strengthen the link between DNA damage and aging, establish Ercc1Δ/- mice as powerful model for identifying interventions to promote healthy aging, reveal untapped potential for reducing endogenous damage, provide new venues for understanding the molecular mechanism of DR, and suggest a counterintuitive DR-like therapy for human progeroid genome instability syndromes and DR-like interventions for preventing neurodegenerative diseases.

2016-09-09 | GSE77321 | GEO

Lifespan extension by diet restriction in DNA repair deficient progeroid Ercc1Δ/- mice [miRNA]

2016-09-09 | GSE77226 | GEO

Disentangling mTOR signalling from the lifespan extending effect of dietary restriction in progeroid DNA-repair deficient mice

Project description:Disentangling mTOR signalling from the lifespan extending effect of dietary restriction in progeroid DNA-repair deficient mice

| PRJNA627185 | ENA

Tissue-specific responses to DNA damage limit function and regulate ageing in progeroid mice

Project description:DNA repair deficiency can lead to segmental phenotypes in humans and mice, in which certain tissues lose homeostasis while others remain seemingly unaffected. This may be due to different tissues facing varying levels of damage or having different reliance on specific DNA repair pathways. However, we find that the cellular response to DNA damage determines different tissue-specific outcomes. Here, we use a mouse model of the human XPF-ERCC1 progeroid syndrome (XFE) caused by loss of DNA repair. We find that p53, a central regulator of the cellular response to DNA damage, regulates tissue dysfunction in Ercc1-/- mice in different ways. We show that ablation of p53 rescues the loss of hematopoietic stem cells, and has no effect on kidney, germ cell or brain dysfunction, but exacerbates liver pathology and polyploidisation. Mechanistically, we find that p53 ablation led to the loss of cell-cycle regulation in the liver, with reduced p21 expression. Eventually, p16/Cdkn2a expression is induced, serving as a fail-safe brake to proliferation in the absence of the p53-p21 axis. Taken together, our data show that distinct and tissue-specific functions of p53, in response to DNA damage, play a crucial role in regulating tissue-specific phenotypes.

2024-02-20 | GSE206778 | GEO

Unprecedented life- and healthspan extension and genome preservation by diet restriction in DNA repair deficient progeroid Ercc1∆/- mice [RNA-seq]

Project description:In this study, we investigate the anti-aging response induced by dietary restriction (DR) on gene expression level. For this, we carried out Ribosomal RNA depleted Total RNA sequencing in 16 weeks old Ercc1∆/- ad libidum (AL), DR and wt mice.

2016-09-09 | GSE77494 | GEO

Increased expression of FOXM1 delays natural and progeroid aging phenotypes

Project description:The FOXM1 member of the forkhead family of transcription factors is known for its pleiotropic C-terminus transcriptional and N-terminus non-transcriptional functions in a wide set of biological processes critical for cellular homeostasis. We previously found that FOXM1 repression during cellular aging accounts for the accrual of senescence phenotypes, which were vastly restored by overexpressing transcriptionally active FOXM1. Here, we found cyclic induction of a N-terminus truncated FOXM1 transgene on progeroid and naturally aged mice, to offset an aging-associated repression of full-length endogenous FoxM1, thereby allowing reinstatement of both transcriptional and non-transcriptional functions. This translated into mitigation of molecular and histopathological progeroid features of progeroid mice, significantly extending its lifespan. Notably, FOXM1 transgene induction also delayed the progressive accumulation of aging phenotypes, while extending the lifespan of naturally aged mice.

2022-01-10 | GSE193147 | GEO

Identify the protein partners of Ercc1 in DNA damage progeria in MEFs

Project description:ERCC1 is a DNA endonuclease participating in the Nucleotide Excision Repair (NER) pathway. Its functionality is related to XPF; the two proteins work as a heterodimer to incise the 5 of a 30-mer that contains the damaged nucleotide and remove the fragment together with XPG. Apart from NER deficiency, mutated Ercc1 in mice and humans causes a series of progeroid symptoms (premature ageing). We hypothesize that there are undescribed functions of ERCC1, possibly in transcriptional regulation that contribute to the development of the striking phenotypes observed. The aim is to identify previously uncharacterized protein partners of ERCC1 that might contribute to our understanding of its differential roles during DNA damage-driven progeria.

2023-10-04 | PXD017063 | Pride

RNA sequencing of mouse hepatic response to lifespan-extending interventions

Project description:This dataset consists of hepatic gene expression profiles of mice subjected to 8 different lifespan-extending interventions, together with the corresponding age-, sex- and strain-matched littermate controls: caloric restriction (CR), methionine restriction (MR), growth hormone receptor knockout (GHRKO), Snell dwarf mice (Pit1 -/-), rapamycin, acarbose, 17-alpha-estradiol (17aE2) and Protandim. Both sexes and different age groups are presented within dataset. Using this data, we identified general and specific gene expression patterns associated with lifespan extension. We detected a feminization effect associated with growth hormone regulation and diminution of sex-related differences in response to many interventions at transcriptome and metabolome levels. Combining the dataset with publicly available resources, we found that many interventions exhibited similar transcriptome changes, whereas some, including rapamycin, showed distinct patterns. We identified common hepatic signatures of lifespan extension, e.g. upregulation of oxidative phosphorylation and NRF2-regulated enzymes, and found that many perturbed pathways are shared across tissues. Moreover, the response of genes related to glucose metabolism and immune function represented both qualitative and quantitative associations with longevity. Finally, we used the detected longevity signatures to identify new candidates for lifespan extension and built GENtervention, a tool that visualizes associations of gene expression responses with lifespan extension.

2019-07-25 | GSE131754 | GEO

Transcriptomic and epigenetic profiling of the pancreata from old mice after transient OSKM activation and recovery

Project description:OSKM activation can restore age-associated features in vitro, and its cyclic transient expression can extend lifespan in progeroid mice. We found that a single period of transient OSKM activation in old mice reconfigures its transcriptome and methylome towards youthful profile

2022-03-07 | GSE155740 | GEO

Transcriptome profiling of NER progeroid animals treated with an NF-kB inhibitor.

Project description:NBD treatment of animals: Sibling pairs of Ercc1-/delta mice housed in a single cage were treated with 8K-NBD or 8K-mNBD 10 mg/kg three times per week intraperitoneally by an investigator blinded as to the treatment group. Treatment began at 5 weeks of age before the animals were symptomatic and continued throughout their lifespan. Mice were euthanized via CO2 inhalation at 12 or 18-20 weeks of age and tissues isolated. 8K-NBD (KKKKKKKKGGTALDWSWLQTE) and inactive 8K-mutant NBD (8K-mNBD) (KKKKKKKKGGTALDASALQTE) were synthesized at the University of Pittsburgh Peptide facility. Peptides were dissolved in DMSO at 40uM and stored at -80 C until dilution in PBS directly before use.

2012-07-01 | E-MEXP-3615 | biostudies-arrayexpress

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