Unprecedented life- and healthspan extension and genome preservation by diet restriction in DNA repair deficient progeroid Ercc1 Δ/- mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus synthetic construct
PROVIDER: GSE77495 | GEO | 2016/09/09
SECONDARY ACCESSION(S): PRJNA310633
REPOSITORIES: GEO
Similar Datasets
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
Project description:Unprecedented life- and healthspan extension and genome preservation by diet restriction in DNA repair deficient progeroid Ercc1 Δ/- mice
| PRJNA310633 | ENA
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
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 | GSE77226 | GEO
Project description:Using these samples, it has been shown that the transcriptional landscape in glomeruli of Ercc1[-/Δ] mice at a rather young age of 14 weeks mimics that of mice which have undergone real-life renal aging. Thus, young Ercc1[-/Δ] mice can be used as a model system for glomerular aging in future studies.
2012-12-21 | GSE43061 | GEO
Project description:Using these samples, it has been shown that the transcriptional landscape in glomeruli of Ercc1[-/Δ] mice at a rather young age of 14 weeks mimics that of mice which have undergone real-life renal aging. Thus, young Ercc1[-/Δ] mice can be used as a model system for glomerular aging in future studies. The RNAs origin from glomerular tissues of mice of 2 distinct genotypes at 3 distinct stages of age. Between 3 and 6 replicates have been prepared per group.
2012-12-21 | E-GEOD-43061 | biostudies-arrayexpress
Project description:Folate is a vitamin required for cell growth and is present in fortified foods in the form of folic acid to prevent congenital abnormalities. The impact of low-folate status on life-long health is poorly understood. We found that limiting folate levels with the folate antagonist methotrexate increased the lifespan of yeast and worms. We then restricted folate intake in aged mice and measured various health metrics, metabolites, and gene expression signatures. Limiting folate intake decreased anabolic biosynthetic processes in mice and enhanced metabolic plasticity. Despite reduced serum folate levels in mice with limited folic acid intake, these animals maintained their weight and adiposity late in life, and we did not observe adverse health outcomes. These results argue that the effectiveness of folate dietary interventions may vary depending on an individual's age and sex. A higher folate intake is advantageous during the early stages of life to support cell divisions needed for proper development. However, a lower folate intake later in life may result in healthier aging.
| S-EPMC11266815 | biostudies-literature
Project description:A high-throughput anti-aging drug screen was developed that simultaneously measures senescence-associated ?-galactosidase activity and proliferation. Applied to replicatively pre-aged fibroblasts, this screen yielded violuric acid (VA) and 1-naphthoquinone-2-monoxime (N2N1) as its top two hits. These lead compounds extended the replicative life spans of normal and progeroid human cells in a dose-dependent manner and also extended the chronological life spans of mice and C. elegans. They are further shown here to function as redox catalysts in oxidations of NAD(P)H. They thus slow age-related declines in NAD(P)+/NAD(P)H ratios. VA participates in non-enzymatic electron transfers from NAD(P)H to oxidized glutathione or peroxides. N2N1 transfers electrons from NAD(P)H to cytochrome c or CoQ10 via NAD(P)H dehydrogenase (quinone) 1 (NQO1). Our results indicate that pharmacologic manipulation of NQO1 activity via redox catalysts may reveal mechanisms of senescence and aging.
| S-EPMC6335401 | biostudies-literature
Project description:Folate is a vitamin required for cell growth and is present in fortified foods in the form of folic acid to prevent congenital abnormalities. The impact of low folate status on life-long health is poorly understood. We found that limiting folate levels with the folate antagonist methotrexate increased the lifespan of yeast and worms. We then restricted folate intake in aged mice and measured various health metrics, metabolites, and gene expression signatures. Limiting folate intake decreased anabolic biosynthetic processes in mice and enhanced metabolic plasticity. Despite reduced serum folate levels in mice with limited folic acid intake, these animals maintained their weight and adiposity late in life, and we did not observe adverse health outcomes. These results argue that the effectiveness of folate dietary interventions may vary depending on an individual's age and sex. A higher folate intake is advantageous during the early stages of life to support cell divisions needed for proper development. However, a lower folate intake later in life may result in healthier aging.
| S-EPMC10802571 | biostudies-literature
Project description:The gut microbiome is emerging as a key regulator of several metabolic, immune and neuroendocrine pathways. Gut microbiome deregulation has been implicated in major conditions such as obesity, type 2 diabetes, cardiovascular disease, non-alcoholic fatty acid liver disease or cancer, but its precise role in aging remains to be elucidated. Here, we characterize the gut microbiome profile of accelerated aging and show that its external modulation is sufficient to extend healthspan and lifespan. We found that two different mouse models of progeria present with intestinal dysbiosis, which is characterized, among other alterations, by an increment in proteobacteria, cyanobacteria and a loss in verrucomicrobia, whereas long-lived humans (i.e., centenarians) exhibit a remarkable increase in verrucomicrobia and a reduction in proteobacteria. Fecal microbiota transplantation proved to be effective to enhance healthspan and lifespan in both progeroid mouse models and, more importantly, the solely transplantation with the verrucomicrobia Akkermansia muciniphila was sufficient to exert beneficial effects. Our results demonstrate that intestinal dysbiosis is a phenotype associated with accelerated aging and its correction provides health benefits. Moreover, metabolomic analysis of ileal content points to the restoration of secondary bile acids as a possible mechanism for the beneficial outcome of reestablishing a healthy microbiome. Our results suggest the existence of a link between gut aging and the microbiota, and can help to gain insight into the rationale for microbiome-based interventions against age-related diseases. Mouse sequence data have been deposited in ENA (https://www.ebi.ac.uk/ena) under accession number PRJEB34214
| EGAS00001003656 | EGA