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Loss of the actin remodeler Eps8 causes calorie restriction and improved metabolic status in mice

ABSTRACT: In a variety of organisms, including mammals, caloric restriction improves metabolic status and lowers the incidence of chronic-degenerative diseases, ultimately leading to increased lifespan. Here we show that knockout mice for Eps8, a regulator of actin dynamics, display reduced bodyweight, partial resistance to age- or diet-induced obesity, and overall improved metabolic status. We present evidence that these phenotypes, which are associated to increased lifespan in the Eps8 null mice, are due to caloric restriction. This, in turn, is caused by reduced intestinal fat absorption, due to altered morphogenesis of microvilli in intestinal enterocytes. In the nematode, genetic removal of Eps8, causes a microvillar phenotype, indistinguishable from that observed in mice, which leads to early larval lethality. By exploiting the nematode model system, we demonstrate here that the actin bundling activity of Eps8 is indispensable for viability and proper intestinal morphogenesis. This result links a precise molecular function of Eps8 to proper microvillar morphogenesis, and therefore to the phenotype of Eps8-null mice. Our results implicate actin dynamics in individual variations in bodyweight, metabolic status and longevity.

ORGANISM(S): Mus musculus

PROVIDER: GSE14454 | GEO | 2010/03/09

SECONDARY ACCESSION(S): PRJNA111565

REPOSITORIES: GEO

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Loss of the actin remodeler Eps8 causes calorie restriction and improved metabolic status in mice

Project description:In a variety of organisms, including mammals, caloric restriction improves metabolic status and lowers the incidence of chronic-degenerative diseases, ultimately leading to increased lifespan. Here we show that knockout mice for Eps8, a regulator of actin dynamics, display reduced bodyweight, partial resistance to age- or diet-induced obesity, and overall improved metabolic status. We present evidence that these phenotypes, which are associated to increased lifespan in the Eps8 null mice, are due to caloric restriction. This, in turn, is caused by reduced intestinal fat absorption, due to altered morphogenesis of microvilli in intestinal enterocytes. In the nematode, genetic removal of Eps8, causes a microvillar phenotype, indistinguishable from that observed in mice, which leads to early larval lethality. By exploiting the nematode model system, we demonstrate here that the actin bundling activity of Eps8 is indispensable for viability and proper intestinal morphogenesis. This result links a precise molecular function of Eps8 to proper microvillar morphogenesis, and therefore to the phenotype of Eps8-null mice. Our results implicate actin dynamics in individual variations in bodyweight, metabolic status and longevity. cDNA expression profiling of liver of 4 mutant EPS8 -/- animals versus pool of 4 wt animals. 8 hybridisation including 4 dye swap experiments

2010-03-09 | E-GEOD-14454 | biostudies-arrayexpress

Circadian expression data from muscle stem cells from adult and aged mice fed with normal diet or calorie restricted

Project description:Caloric restriction (CR) enhances the function of adult stem cells and significantly extends the lifespan of many organisms including rodents. CR increases the expression of Period genes in several tissues in mice, and the circadian machinery is strongly influenced by feeding and metabolic pathways. Importantly, Bmal1-deficient mice, or Period/Timeless-deficient Drosophila are refractory to the lifespan extension induced by CR. We therefore studied whether CR could prevent the ageing related circadian reprogramming we had observed in muscle SCs.

2017-08-10 | GSE84522 | GEO

Circadian expression data from epidermal stem cells from adult and aged mice fed with normal diet or calorie restricted

2017-08-10 | GSE84521 | GEO

CDK1-formin signal confers microvillar effacement by an attaching and effacing (A/E) pathogen

Project description:Enterohemorrhagic Escherichia coli (EHEC) induces the attachment and effacement of intestinal microvilli. While the molecular mechanisms contributed to the attachment of EHEC have been thoroughly studied, the underlying mechanisms for the effacement of intestinal microvilli induced by EHEC remained elusive. By focus RNAi screening and genetic analysis in C. elegans and further reconfirmed in human Caco-2 intestinal epithelial cells, we demonstrate that the CDK1-formin signal axis is required for this EHEC-induced microvillar effacement in vitro and in vivo.

2020-11-11 | GSE142507 | GEO

SIRT1 but not its increased expression is essential for lifespan extension in caloric restricted mice.

Project description:The SIRT1 deacetylase is one of the best-studied potential mediators of some of the anti-aging effects of calorie restriction (CR); but its role in CR-dependent lifespan extension has not been demonstrated. We previously found that mice lacking both copies of SIRT1 displayed a shorter median lifespan than wild type mice on an ad libitum diet. Here we report that median lifespan extension in CR heterozygote SIRT1+/- mice was identical (51%) to that observed in wild type mice but SIRT1+/- mice displayed a higher frequency of some certain pathologies. Although larger studies in different genetic backgrounds are necessary , these results provide strong initial evidence for the requirement of SIRT1 for the anti-aging effects of CR, but suggest that its high expression is not required for CR-induced lifespan extension. Key words: SIRT1, caloric restriction, lifespan, anti-aging 2-5 month old male mice of 3 different genotypes (SIRT1+/+, SIRT1+/-, and SIRT1-/-) that had normal, reduced or no expression of SIRT1 were treated with either a 40% caloric restricted diet (CR) or an ad libitum diet (AL). 2-4 replicates of each experimental condition were used in the analysis.

2014-04-25 | E-GEOD-46895 | biostudies-arrayexpress

RNA-seq analysis of Caenorhabditis elegans Transcriptomes after fed with D-mannose

Project description:we used Caenorhabditis elegans as a model organism, to investigate the effect of mannose on the lifespan. Using nematode RNAi methods, RT-PCR, RNA-seq and other experimental method, we explored the possible mechanism for how mannose change the lifespan of Caenorhabditis elegans.

2023-09-01 | GSE192579 | GEO

Circadian alignment of early onset caloric restriction promotes longevity in male C57BL/6J mice

Project description:Caloric restriction (CR) prolongs lifespan, yet the mechanisms by which it does so remain poorly understood. Under CR, mice self-impose chronic cycles of 2-hour-feeding and 22-hour-fasting, raising the question whether calories, fasting, or time of day are causal. We show that 30%-CR is sufficient to extend lifespan 10%; however, a daily fasting interval and circadian-alignment of feeding act together to extend lifespan 35% in male C57BL/6J mice. These circadian effects of CR are independent of fasting duration and body weight. Aging induces widespread increases in gene expression associated with inflammation and decreases in expression of genes encoding components of metabolic pathways in liver from ad lib fed mice. CR at night ameliorates these aging-related changes. Thus, circadian interventions promote longevity and provide a perspective to further explore mechanisms of aging.

2022-05-06 | GSE190939 | GEO

Mus musculus

Project description:Loss of the actin remodeler Eps8 causes calorie restriction and improved metabolic status in mice

| PRJNA111565 | ENA

Improvements in health, not survival, by late-onset metformin treatment

Project description:The biguanide metformin improves health and survival in male mice; however, it is unclear whether metformin will confer health and lifespan benefits to mice when started late in life. Two year-old mice fed on standard chow were treated with 1% metformin every-other week (EOW) or two consecutive weeks per month (2WM). EOW mice displayed improvements in healthspan reminiscent of mice on caloric restriction. The age-associated histopathological changes in liver and kidney were significantly reduced in EOW compared to 2WM or control mice. Some of the affected gene transcripts and metabolites were found to be risk predictors of metabolic disorder. Neither EOW nor 2WM mice exhibited extension in mean or maximum lifespan compared with control animals. Thus, metformin supplementation had a strong impact on reversing some of the deleterious effects of aging and resulted in an improvement of health in old male mice in the absence of an extension of lifespan.

2018-02-23 | GSE97074 | GEO

Phenotypic profiling of adaptation to oxidative stress

Project description:Caloric restriction extends lifespan, an effect once thought to involve attenuation of reactive oxygen species (ROS) generated by aerobic metabolism. However, recent evidence suggests that caloric restriction may in fact raise ROS levels, which in turn provides protection from acute doses of oxidant through a process called adaptation. To shed light on the molecular mechanisms of adaptation, we designed a series of genome-wide deletion fitness screens to identify genes involved in adaptation to hydrogen peroxide.

2009-04-23 | GSE12733 | GEO

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