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Genetic regulation of life span, metabolism, and body weight in Pohn, a new wild-derived mouse strain.

ABSTRACT: Quantitative trait loci (QTL) of longevity identified in human and mouse are significantly colocalized, suggesting that common mechanisms are involved. However, the limited number of strains that have been used in mouse longevity studies undermines the ability to identify longevity genes. We crossed C57BL/6J mice with a new wild-derived strain, Pohn, and identified two life span QTL-Ls1 and Ls2. Interestingly, homologous human longevity QTL colocalize with Ls1. We also defined new QTL for metabolic heat production and body weight. Both phenotypes are significantly correlated with life span. We found that large clone ratio, an in vitro indicator for cellular senescence, is not correlated with life span, suggesting that cell senescence and intrinsic aging are not always associated. Overall, by using Pohn mice, we identified new QTL for longevity-related traits, thus facilitating the exploration of the genetic regulation of aging.

SUBMITTER: Yuan R

PROVIDER: S-EPMC3598364 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Genetic regulation of life span, metabolism, and body weight in Pohn, a new wild-derived mouse strain.

Yuan Rong R Flurkey Kevin K Meng Qingying Q Astle Mike C MC Harrison David E DE

The journals of gerontology. Series A, Biological sciences and medical sciences 20120508 1

Quantitative trait loci (QTL) of longevity identified in human and mouse are significantly colocalized, suggesting that common mechanisms are involved. However, the limited number of strains that have been used in mouse longevity studies undermines the ability to identify longevity genes. We crossed C57BL/6J mice with a new wild-derived strain, Pohn, and identified two life span QTL-Ls1 and Ls2. Interestingly, homologous human longevity QTL colocalize with Ls1. We also defined new QTL for metabo ...[more]

PMID: 22570136

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Project description:In this study we used the cre-loxP recombinase system. All mice were genetically modified in as much as all mice had exon 4 of the IGF-I gene flanked by loxP sites. In the knockouts, Mx-Cre had also been introduced, which results in inactivation of the IGF-I gene specifically in the liver. RNA from liver, skeletal muscle, heart, fat (retroperitoneal fat) and bone (vertebrae) was extracted from 6 control and 7 mice deficient of liver-derived insulin-like growth factor-I (LI-IGF-I-/- mice) by Tri Reagent (Sigma, St. Louis, MO, USA) and purified using spin columns from Rneasy Total RNA Isolation Kit (Qiagen, Chatsworth, CA, USA). For microarray analysis, the RNA samples were pooled three or two, resulting in three pools per group while for the confirmatory RT-PCR analyses individual mice (n=6-7) were analyzed. For each organ, there were three pooled samples from the mice with deficiency of liver-derived IGF-I and 3 pooled samples from the wildtype mice i.e. intact IGF-I gene. The pooled RNA was reverse transcribed into cDNA, labeled, and analyzed by DNA microarray (MG-U74Av2 Array; Affymetrix, Santa Clara, CA, USA). Scanned output files were analyzed using Affymetrix Micro Array Suite version 4.0.1 software (Affymetrix). To allow comparison of gene expression, the gene chips were globally scaled to an average intensity of 500. Each of the three LI-IGF-I-/- chips was compared with the three control chips, generating a total of nine comparison files. Only the genes that were regarded as M-^SchangedM-^T according to the Affymetrix algorithm in four to nine of the comparisons were selected for further analysis. We then calculated an average-fold change for the nine comparisons of the selected genes. For a gene to be regarded as consistently regulated in the LI-IGF-I-/- mice, the average-fold increase or decrease of the nine comparisons was set as at least 1.5 fold in at least 4 of the 5 analyzed organs. Microarray showed that heat shock protein 1A (Hspa1a), heat shock protein 1B (Hspa1b), and connective tissue growth factor (Ctgf) were decreased in all organs that expressed these genes. CCAAT/enhancer protein delta (Cebpd) decreased in 4 of the 5 analyzed organs. The RT-PCR analyses that were performed later confirmed that mRNA levels of Hspa1a, Hspa1b, and Ctgf decreased in LI-IGF-I-/- mice in skeletal muscle tissue while mRNA levels of Cebpd were unchanged.

Dataset Information

Genetic regulation of life span, metabolism, and body weight in Pohn, a new wild-derived mouse strain.

Publications

Genetic regulation of life span, metabolism, and body weight in Pohn, a new wild-derived mouse strain.

Similar Datasets

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