Effect of age, calorie restriction and resveratrol on gene expression in mouse heart, brain, and skeletal muscle
ABSTRACT: Resveratrol in high doses has been shown to extend lifespan in some studies in invertebrates and to prevent early mortality in mice fed a high-fat diet. We fed mice from middle age (14-months) to old age (30-months) either a control diet, a low dose of resveratrol (4.9 mg kg-1 day-1), or a calorie restricted (CR) diet and examined genome-wide transcriptional profiles. We report a striking transcriptional overlap of CR and resveratrol in heart, skeletal muscle and brain. Both dietary interventions inhibit gene expression profiles associated with cardiac and skeletal muscle aging. Gene expression profiling suggests that both CR and resveratrol may retard some aspects of aging through alterations in chromatin structure and transcription. Resveratrol, at doses that can be readily achieved in humans, fulfills the definition of a dietary compound that mimics some aspects of CR. Keywords: aging intervention study Overall design: Heart, neocortex tissue, and gastrocnemius muscle was collected from young and old mice at 5 and 30 months of age, respectively; mice were subjected to either a calorie restricted diet or a control diet supplemented with resveratrol
Project description:Resveratrol in high doses has been shown to extend lifespan in some studies in invertebrates and to prevent early mortality in mice fed a high-fat diet. We fed mice from middle age (14-months) to old age (30-months) either a control diet, a low dose of resveratrol (4.9 mg kg-1 day-1), or a calorie restricted (CR) diet and examined genome-wide transcriptional profiles. We report a striking transcriptional overlap of CR and resveratrol in heart, skeletal muscle and brain. Both dietary interventions inhibit gene expression profiles associated with cardiac and skeletal muscle aging. Gene expression profiling suggests that both CR and resveratrol may retard some aspects of aging through alterations in chromatin structure and transcription. Resveratrol, at doses that can be readily achieved in humans, fulfills the definition of a dietary compound that mimics some aspects of CR. Experiment Overall Design: Heart, neocortex tissue, and gastrocnemius muscle was collected from young and old mice at 5 and 30 months of age, respectively; mice were subjected to either a calorie restricted diet or a control diet supplemented with resveratrol
Project description:Calorie restriction (CR) has been shown to extend life- and health-span in model species. For most humans, a life-long CR diet is too arduous to adhere to. The aim of this study was to explore whether weekly intermittent CR can 1) provide long-term beneficial effects and 2) counteract diet-induced obesity in male aging mice. In this study, we have exposed C57Bl/6J mice for 24 months to an intermittent (INT) diet, alternating weekly between CR of a control diet and ad libitum moderate-fat (MF) feeding. This weekly intermittent CR significantly counteracted the adverse effects of the MF diet on mortality, body weight and liver health markers in male 24-month-old mice. Hepatic gene expression profiles of INT-exposed animals appeared much more comparable to CR than to MF-exposed mice. At 12 months of age, a subgroup of MF-exposed mice was transferred to the INT diet. Gene expression profiles in the liver of the 24-month-old diet switch mice were highly similar to the INT-exposed mice. However, a small subset of genes was consistently changed by the MF diet during the first phase of life. Weekly intermittent CR largely, but not completely, reversed adverse effects caused by a MF diet. Overall design: Male C57Bl/6J mice were divided to 3 dietary intervention groups: Control (AIN-93W), 30% calorie restriction (CR; AIN-93W-CR) and medium fat (MF; AIN-93W-MF; 25% energy from fat). Dietary interventions started at the age of 9 weeks and sacrifice was performed at the age of 6, 12, 24 and 28 months. We performed various measurements on metabolic parameters and gene expression analysis. This entry represents the microarray data. The array data from the 6-, 12- and 24-month-old mice exposed to the Control, CR and MF diet have been published before, and are also available under GEO accession number GSE84495.
Project description:Diminishment of colonic health is associated with various age-related pathologies. Calorie restriction (CR) is an efficient strategy to increase healthy lifespan, although underlying mechanisms are not fully elucidated. Here we report the effects of lifelong CR on markers of colonic health in aging mice. We show that 30% energy reduction, as compared to a control (C) and moderate-fat (MF) diet, is associated with attenuated immune-related gene expression and lower levels of bile acids in the colon. Pronounced shifts in microbiota composition, together with lowered plasma levels of interleukin 6, in mice exposed to CR are in line with these findings. Furthermore, expression of genes involved in lipid metabolism was higher upon CR as compared to C and MF, pointing towards efficient regulation of energy metabolism. Switching from CR to an ad libitum MF diet at old age revealed remarkable phenotypic plasticity, although expression of a small subset of genes remained CR-associated. This research demonstrates that CR beneficially affects markers of colonic health in aging mice and as such may attenuate the progressive age-related decline in health. Overall design: Male C57BL/6J mice were randomized to different dietary regimens starting at the age of 9 weeks. Mice were lifelong fed either a semi-synthetic control diet consisting of 10E% of fat (C), a CR diet without malnutrition (30% energy reduction compared to the C diet) or a moderate-fat (MF) diet consisting of 25E% of fat. All diets, except the CR diet, were fed ad libitum. A subgroup of mice on CR was switched to the MF diet at the age of 24 months until sacrifice at 28 months. Upon sacrifice at 6 or 28 months of age, colonic scrapings were collected and RNA was isolated for microarray analyses.
Project description:SCOPE: We investigated whether a novel dietary intervention consisting of an every-other-week calorie-restricted diet could prevent nonalcoholic fatty liver disease (NAFLD) development induced by a medium-fat (MF) diet. METHODS AND RESULTS: Nine-week-old male C57BL/6J mice received either a (i) control (C), (ii) 30E% calorie restricted (CR), (iii) MF (25E% fat), or (iv) intermittent (INT) diet, a diet alternating weekly between 40E% CR and an ad libitum MF diet until sacrifice at the age of 12 months. The metabolic, morphological, and molecular features of NAFLD were examined. The INT diet resulted in healthy metabolic and morphological features as displayed by the continuous CR diet: glucose tolerant, low hepatic triglyceride content, low plasma alanine aminotransferase. In contrast, the C- and MF-exposed mice with high body weight developed signs of NAFLD. However, the gene expression profiles of INT-exposed mice differed to those of CR-exposed mice and showed to be more similar with those of C- and MF-exposed mice with a comparable body weight. CONCLUSIONS: Our study reveals that the INT diet maintains metabolic health and reverses the adverse effects of the MF diet, thus effectively prevents the development of NAFLD in 12-month-old male C57BL/6J mice. Male C57Bl/6J mice were divided to 4 dietary intervention groups: Control (AIN-93W), 30% calorie restriction (CR; AIN-93W-CR), medium fat (MF; AIN-93W-MF; 25% energy from fat) and intermittent diet (INT; weekly alternating diet between AIN-93W-MF ad lib and 40% CR of AIN-93W). We performed various measurements on metabolic parameters and gene expression analysis on the liver. This entry represents the microarray data of the liver gene expression of each mouse.
Project description:Calorie restriction (CR) consistently extends longevity and delays age-related diseases across several animal models. We have previously shown that different dietary fat sources can modulate life span and mitochondrial ultrastructure, function and membrane fatty acid composition in mice maintained on a 40% CR. In particular, animals consuming lard as the main fat source (CR-Lard) lived longer than CR mice consuming diets with soybean oil (CR-Soy) or fish oil (CR-Fish) as the predominant lipid source. In the present work, a transcriptomic analysis in liver and skeletal muscle was performed in order to elucidate possible mechanisms underlying the changes in energy metabolism and longevity induced by dietary fat in CR mice. After 8 months of CR, transcription downstream of several mediators of inflammation was inhibited in liver. In contrast, proinflammatory signaling was increased in the CR-Fish versus other CR groups. Dietary fish oil induced a gene expression pattern consistent with increased transcriptional regulation by several cytokines (TNF, GM-CSF, TGF-b) and sex hormones when compared to the other CR groups. The CR-Fish also had lower expression of genes involved in fatty acid biosynthesis and increased expression of mitochondrial and peroxisomal fatty acid b-oxidation genes than the other CR diet groups. Our data suggest that a diet high in n-3 PUFA, partially reverts CR-related changes in gene expression of key processes, such as inflammation and steroid hormone signaling, and this may mitigate life span extension with CR in mice consuming diets high in fish oil. Sixteen male C57BL/6 mice were purchased at 14 weeks of age from the Jackson Laboratory (Sacramento, CA) and fed a commercial rodent chow diet (Harlan Teklad #7012). The mice were allowed ad libitum access to food and their food intake was monitored for two weeks. At 4 months of age, the animals were randomly assigned to four groups. The Control group received 95% of the daily ad libitum caloric intake (13.6 kcal/day) to avoid excessive weight gain and obesity, and the other three groups received 60% of the ad libitum consumption (8.6 kcal/day). A total of 31 mice samples (eight control, eight fish, eight lard and seven soy distributed in liver (n=16) and muscle (n=15) tissues) were analyzed by RNA-Sequencing. However, 2 samples (1071 control liver [JFM42H], 1125 fish muscle [JFM45D]) were discarded for further analysis after performing cluster analysis (they were clustering in a different groups). Also their RIN values were not as high as those of the other samples, indicating lower quality of the RNA.
Project description:Feeding resveratrol to Drosophila melanogaster extends lifespan. Studies of microarray show similarities between calorie/dietary restriction and resveratrol on both a gene expression and biological pathway level. 9 samples: 3 biological replicates each of normal diet, restricted diet and normal diet plus resveratrol
Project description:Feeding resveratrol to Drosophila melanogaster extends lifespan. Studies of microarray show similarities between calorie/dietary restriction and resveratrol on both a gene expression and biological pathway level. Overall design: 9 samples: 3 biological replicates each of normal diet, restricted diet and normal diet plus resveratrol
Project description:Dietary interventions are effective ways to extend or shorten lifespan. By examining midlife hepatic gene expressions in mice under different dietary conditions, which resulted in different lifespans and aging-related phenotypes, we were able to identify genes and pathways that modulate the aging process. We found that pathways transcriptionally correlated with diet-modulated lifespan and physiological changes were enriched for lifespan-modifying genes. Male C57BL/6J mice at 4 weeks of age were purchased from Shanghai Animal Co, Ltd. Mice were maintained under a 12-hour dark/light cycle (lights on at 6:30 am) at a temperature of 22 ± 3 °C in accredited animal facilities. Prior to the start of experiment, mice were maintained on a low-fat diet (Research Diets Inc., New Brunswick, NJ) for one week. At the age of 5 weeks, animals were randomly assigned to one of the 6 intervention groups (n = 30 for each group): feeding of a low-fat diet (10% fat, D12450B, Research Diets) ad libitum (LF) or with 30% calorie restriction (LF+CR) or with voluntary running exercise (LF+Ex), feeding of a high-fat diet (60% fat, D12492, Research Diets) ad libitum (HF) or with 30% calorie restriction (HF+CR) or with voluntary running exercise (HF+Ex). All mice were housed individually during the study. The daily consumption of food in LF and HF groups was recorded over a week and averaged to determine the amount of food for the following week for the LF+CR and HF+CR groups, respectively. After 1 week acclimation in cage with the locked running wheels, mice in the LF+Ex and HF+Ex groups were allowed free access to a running wheel, and the running distance and time were recorded automatically by the equipment. The hepatic transcriptional level for 3 mice from each intervention group at 62 weeks of age was analyzed using Affymetrix Mouse Genome 430 2.0 Arrays.
Project description:Calorie restriction (CR) enhances longevity and mitigates aging phenotypes in numerous species. Physiological responses to CR are cell-type specific and variable throughout the lifespan; however, the mosaic of molecular changes responsible CR benefits remain unclear, particularly in brain regions susceptible to deterioration throughout aging. Thus, we examined the influence of long-term CR on the CA1 hippocampal region, a key learning and memory brain area that is vulnerable to age-related pathologies, such as Alzheimer’s disease (AD). Through mRNA sequencing and NanoString nCounter analysis, we demonstrate that one year of CR feeding suppresses an age-dependent signature of 882 genes functionally associated with synaptic transmission-related pathways, including calcium signaling, long-term potentiation (LTP), and Creb signaling in wild-type mice. By comparing the influence of CR on hippocampal CA1 region transcriptional profiles at younger- (5 months) and older-adult (15 months) timepoints, we identify conserved upregulation of proteome quality control and calcium buffering genes, including heat shock 70 kDa proteins 1b and 5 (Hspa1b and Hspa5), protein disulfide isomerase family A members 4 and 6 (Pdia4 and Pdia6), and calreticulin (Calr). Expression levels of putative neuroprotective factors, klotho (Kl) and transthyretin (Ttr), are also elevated by CR throughout adulthood, although the global CR-specific expression profiles at young and older timepoints are highly divergent. At a previously unachieved resolution, our results demonstrate conserved activation of neuroprotective gene signatures and broad CR-suppression of age-dependent hippocampal CA1 region expression changes, indicating that CR functionally maintains a more youthful transcriptional state within hippocampal CA1 throughout aging. Hippocampal CA1 region mRNA profiles of younger- (5 months) and older-adult (15 months) mice on calorie-restricted (CR) and normal (AD) diets were generated by deep sequencing using Illumina HiSeq 2500.
Project description:Using high-throughput deep sequencing, microRNA expression was profiled across six dietary intervention groups, including low fat (LF) or high fat (HF) with or without calorie restriction (LF+CR, HF+CR) or exercise (LF+Ex, HF+Ex). Overall design: Mice were treated starting at 5 weeks of age with LF or HF diet with or without CR or Ex. Liver RNA was extracted and used for small RNA-sequencing at midlife (62 weeks of age).