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A Comparison of Gene Expression Profiles of Rat Tissues after Mild and Short-Term Calorie Restrictions.

ABSTRACT: Many studies have shown the beneficial effects of calorie restriction (CR) on rodents' aging; however, the molecular mechanism explaining these beneficial effects is still not fully understood. Previously, we conducted transcriptomic analysis on rat liver with short-term and mild-to-moderate CR to elucidate its early response to such diet. Here, we expanded transcriptome analysis to muscle, adipose tissue, intestine, and brain and compared the gene expression profiles of these multiple organs and of our previous dataset. Several altered gene expressions were found, some of which known to be related to CR. Notably, the commonly regulated genes by CR include nicotinamide phosphoribosyltransferase and heat shock protein 90, which are involved in declining the aging process and thus potential therapeutic targets for aging-related diseases. The data obtained here provide information on early response markers and key mediators of the CR-induced delay in aging as well as on age-associated pathological changes in mammals.

SUBMITTER: Saito K

PROVIDER: S-EPMC8308279 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:With the population of older and overweight individuals on the rise in the Western world, there is an ever greater need to slow the aging processes and reduce the burden of age-associated chronic disease that would significantly improve the quality of human life and reduce economic costs. Caloric restriction (CR), is the most robust and reproducible intervention known to delay aging and to improve healthspan and lifespan across species (1); however, whether this intervention can extend lifespan in humans is still unknown. Here we report that rats and humans exhibit similar responses to long-term CR at both the physiological and molecular levels. CR induced broad phenotypic similarities in both species such as reduced body weight, reduced fat mass and increased the ratio of muscle to fat. Likewise, CR evoked similar species-independent responses in the transcriptional profiles of skeletal muscle. This common signature consisted of three key pathways typically associated with improved health and survival: IGF-1/insulin signaling, mitochondrial biogenesis and inflammation. To our knowledge, these are the first results to demonstrate that long-term CR induces a similar transcriptional profile in two very divergent species, suggesting that such similarities may also translate to lifespan-extending effects in humans as is known to occur in rodents. These findings provide insight into the shared molecular mechanisms elicited by CR and highlight promising pathways for therapeutic targets to combat age-related diseases and promote longevity in humans. Male Fisher 344 rats (n=54) were randomly assigned to two groups at 2 months of age. One group was kept ad libitum (AL) fed throughout their lifespan while the calorie restriction (CR) group was progressively brought down to a 40% CR. All animals were fed a NIH-31 standard chow (Harlan Teklad, Indianapolis, IN, USA). Rats were singly housed in an environmentally controlled vivarium with unlimited access to water and a controlled photoperiod (12 hr. light;12 hr. dark). Body weights and food intake were recorded biweekly. All rats were maintained between 68-72M-BM-0F according to animal protocols and NIH guidelines. Total RNA was extracted from the vastus lateralis skeletal muscle using Trizol Reagent (Invitrogen, Carlsbad, CA) following the manufacturerM-bM-^@M-^Ys instructions, n=5 from each group. Total RNA samples were biotin labeled and hybridized to RatRef-12 v1 Gene Expression beadchips (Illumina, San Diego, CA) following Illumina protocols. Arrays were washed and scanned using an Illumina BeadArray 500GX reader. Microarray florescent signals were extracted using the Illumina GenomeStudio Gene Expression software(v1.6.0) and any spots at or below the background were filtered using an Illumina detection p-value of 0.02 and above. The natural log of all remaining scores were used to find the avg and std of each array and the z-score normalization was calculated . Correlation analysis, sample clustering analysis and principal component analysis include all of probes are performed to identify/exclude any possible outliners. The resulting dataset was next analyzed with DIANE 6.0, a spreadsheet based microarray analysis program. Gene set enrichment analysis use gene expression values or gene expression change values for all of the genes in the microarray. Parametric analysis of gene set enrichment (PAGE) was used [pubmed 20682848] for gene set analysis. Gene Sets include the MSIG database [Link], Gene Ontology Database [Link], GAD human disease and mouse phenotype gene sets [pubmed: 20092628] were used to explore functional level changes.

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A Comparison of Gene Expression Profiles of Rat Tissues after Mild and Short-Term Calorie Restrictions.

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