SIRT1 but not its increased expression is essential for lifespan extension in caloric restricted mice.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE46895 | GEO | 2014/04/25
SECONDARY ACCESSION(S): PRJNA202976
REPOSITORIES: GEO
Similar Datasets
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
Project description:Calorie restriction (CR) is the most robust non-genetic intervention to universally delay the onset of age-related diseases and extend mean and maximum lifespan. However, species, strain, sex, diet, age of onset, and level of CR are emerging as important variables to consider for a successful CR response. Here, we investigated the role of strain, sex and level of CR on outcomes of health and survival in mice. Response to CR varied from lifespan extension to no effect on survival, while consistently delaying the onset and impact of diseases independently of strain, sex and level of dietary restriction. CR led to transcriptional and metabolomics changes in the liver indicating anaplerotic filling of the Krebs cycle together with fatty acid fueling of mitochondria. Additionally, CR prevented the age-associated decline in the proteostasis network. Further, CR increased mitochondrial number and preserved their ultrastructure and function with age. Abrogation of mitochondrial function by deletion of fumarate hydratase or malate dehydrogenase 2 negated the life-prolonging effects of CR in yeast and worms. In F1 hybrid strains of mice, the lifespan response to CR tracked with the dam, indicating that the mitochondrial haplotype is an important regulator of CR. Our data illustrate the complexity of the CR responses within a single animal species in the context of aging, with a clear separation of outcomes related to health and survival, highlighting the complexities of translation of CR into human interventions. The study examines the effects of sex (male/female), mouse strain (DBA2/J versus C57BL/J), and diet (Ad libitum, 20% caloric restriction (20%CR), or 40%CR) using six biological replicate samples per group.
2016-06-27 | E-GEOD-81959 | biostudies-arrayexpress
Project description:Calorie restriction (CR) extends lifespan by modulating the mechanisms involved in aging. We quantified the hepatic proteome of male C57BL/6 mice exposed to graded levels of CR (0% to 40% CR) for three months, and evaluated which signaling pathways were most affected.
2023-10-24 | PXD033436 | Pride
Project description:Background: Calorie restriction (CR) is the only intervention known to extend lifespan in a wide range of organisms, including mammals. However, the mechanisms by which it regulates mammalian aging remain largely unknown and the involvement of the TOR and Sirtuin pathways (which regulate aging in lower organisms) remain controversial. Femaleness is a second phenotype generally associated with longevity but the relationship between sex-biased and CR-induced gene expression remains undetermined. Methodology/Principal Findings: We generated microarray gene expression data from livers of male mice fed high calorie or CR diets, and we find that CR significantly changes the expression of over 3,000 genes, many between 10- and 50-fold. We compare our data to the GenAge database of known aging-related genes and to prior microarray expression data of genes expressed differently between male and female mice. CR generally feminizes gene expression and many of the most significantly changed individual genes are involved in aging, hormone signaling, and p53-associated regulation of the cell cycle and apoptosis. Among the genes showing the largest and most statistically significant CR-induced expression differences are Ddit4, a key regulator of the TOR pathway, and Nnmt, a regulator of lifespan linked to the Sirtuin pathway. Using Western analyses, we confirmed post-translational inhibition of the TOR pathway. Conclusions: Our data show that CR induces widespread gene expression changes and acts through highly evolutionarily conserved pathways, from microorganisms to mammals, and that its life-extension effects might arise partly from a shift toward a gene expression profile more typical of the longer-lived female sex. Keywords: Two-class gene expression comparison. Calorie restriction (CR) versus HIGH CALORIE feeding. Design of the experiment is a two-class paired design in which the two classes are HIGH CALORIE and CALORIE RESTRICTION (CR) dietary regimens fed to mice, resulting in 15 HIGH CALORIE microarrays and 8 CR microarrays; 23 total microarrays. Four HIGH CALORIE and 2 CR microarrays were produced using pools of 3 RNA samples for each microarray (6 pools of 3, plus 17 individual samples = 35 individual mouse liver samples, 23 microarrays). Total liver RNA was labeled directly. Reference RNA: Stratagene Universal Mouse Reference RNA.
2008-12-30 | E-GEOD-11244 | biostudies-arrayexpress
Project description:Calorie restriction (CR) increases lifespan and improves brain health in mice. Ad libitum low protein, high carbohydrate (LPHC) diets also extend lifespan, but it is not known whether they are beneficial for brain health. We compared hippocampus biology and memory in mice subjected to 20% CR or provided ad libitum access to one of three LPHC diets, or to a control diet. At age 15 months, patterns of RNA expression in the hippocampus were similar between CR and LPHC diets for genes associated with longevity, cytokines and dendrite morphogenesis. Nutrient sensing proteins including SIRT1, mTOR and PGC1α were also influenced by diet, however the effects varied by sex. CR and LPHC diets were associated with increased dendritic spines in dentate gyrus neurons. CR and LPHC diets led to modest improvements in the Barnes Maze and Novel Object Recognition. LPHC diets recapitulate some of the benefits of CR on brain aging.
2018-10-18 | GSE111778 | GEO
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
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 epidermal SCs.
2017-08-10 | GSE84521 | GEO
Project description:Caloric restriction (CR) can delay morbidity and mortality in a broad range of species, including mice and macaques. Mutations and chemical agents, such as resveratrol or rapamycin that partly mimic the CR effect, can similarly increase survival or extend lifespan. In humans, however, the effects of CR or other life-extending agents have not been investigated systematically. Humans already display lower mortality and greater maximal lifespan compared to closely related species, including chimpanzees and macaques. It is thus possible that humans, during their evolution, have acquired genetic mutations mimicking the CR effect. To address this question, we compared transcriptome differences between humans and other primates, with transcriptome changes observed in mice subjected to CR [see references below]. We show that the human transcriptome state examined in multiple tissues and across different ages resembles the transcriptome state of mice fed ad libitum, relative to CR mice or mice treated with resveratrol. Furthermore, transcriptome changes induced by CR were enriched among genes showing age-related changes among primates, concentrated in specific expression patterns, and could be linked with specific functional pathways, including insulin signalling, cancer, and immune response. These findings indicate that the evolution of human longevity was likely independent of CR-induced lifespan extension mechanisms. Consequently, application of CR or CR-mimicking agents may offer a promising direction in the extension of healthy human lifespan. References for the transcriptome changes observed in mice subjected to CR: 1) Barger JL, Kayo T, Vann JM, Arias EB, Wang J, Hacker TA, Wang Y, Raederstorff D, Morrow JD, Leeuwenburgh C, et al: A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One 2008, 3:e2264. 2) Tsuchiya T, Dhahbi JM, Cui X, Mote PL, Bartke A, Spindler SR: Additive regulation of hepatic gene expression by dwarfism and caloric restriction. Physiol Genomics 2004, 17:307-315. 3) Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, et al: Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006, 444:337-342. We collected post-mortem brain, heart, and liver samples from 16 human, 16 chimpanzee and 4 rhesus macaque seperately. All these individuals are adults. RNA extracted from the dissected tissue was hybridized to AffymetrixM-BM-. Human Gene 1.0 ST arrays to quantify gene expression level. We collected prefrontal cortex tissues of mice with age ranging from postnatal 2 days to 2.5 years. The strain of the mice is C57BL/6. RNA extracted from the dissected tissue was hybridized to AffymetrixM-BM-. Mouse Gene 1.0 ST Arrays to quantify gene expression level.
2013-02-28 | E-GEOD-44147 | biostudies-arrayexpress
Project description:Although caloric restriction (CR) was first shown to extend the lifespan of rodents over 75 years ago, the underlying mechanisms remain unclear. Additionally, the majority of published studies have focused on the effects of short-term CR. To better understand cell signaling alterations in a tissue known to be highly impacted by CR, we sought to assess the impact of aging and lifelong CR on skeletal muscle protein phosphorylation dynamics. We performed phosphoproteomic analysis on skeletal muscle from young mice, old mice fed on an ad libitum diet, and old mice fed a CR diet. This analysis revealed distinct phosphoproteomic signatures associated with both aging and diet. Importantly, CR appeared to promote a signature that was more similar to young mice than old mice fed on an ad lib diet. From the phosphorylation measurements on its known substrates, we deciphered that aging promotes Protein kinase A (PKA) signaling, and CR inhibits this signaling cascade. Given the demonstrated role of PKA signaling as a “pro-aging” pathway in various model organisms, including yeast and mice, we propose that CR exerts its longevity-enhancing effects partially via the suppression of this pathway.
2021-01-30 | PXD018455 | JPOST Repository
Project description:Caloric restriction (CR) can delay morbidity and mortality in a broad range of species, including mice and macaques. Mutations and chemical agents, such as resveratrol or rapamycin that partly mimic the CR effect, can similarly increase survival or extend lifespan. In humans, however, the effects of CR or other life-extending agents have not been investigated systematically. Humans already display lower mortality and greater maximal lifespan compared to closely related species, including chimpanzees and macaques. It is thus possible that humans, during their evolution, have acquired genetic mutations mimicking the CR effect. To address this question, we compared transcriptome differences between humans and other primates, with transcriptome changes observed in mice subjected to CR [see references below]. We show that the human transcriptome state examined in multiple tissues and across different ages resembles the transcriptome state of mice fed ad libitum, relative to CR mice or mice treated with resveratrol. Furthermore, transcriptome changes induced by CR were enriched among genes showing age-related changes among primates, concentrated in specific expression patterns, and could be linked with specific functional pathways, including insulin signalling, cancer, and immune response. These findings indicate that the evolution of human longevity was likely independent of CR-induced lifespan extension mechanisms. Consequently, application of CR or CR-mimicking agents may offer a promising direction in the extension of healthy human lifespan. References for the transcriptome changes observed in mice subjected to CR: 1) Barger JL, Kayo T, Vann JM, Arias EB, Wang J, Hacker TA, Wang Y, Raederstorff D, Morrow JD, Leeuwenburgh C, et al: A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One 2008, 3:e2264. 2) Tsuchiya T, Dhahbi JM, Cui X, Mote PL, Bartke A, Spindler SR: Additive regulation of hepatic gene expression by dwarfism and caloric restriction. Physiol Genomics 2004, 17:307-315. 3) Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, et al: Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006, 444:337-342.
2013-02-28 | GSE44147 | GEO