Global expression profiles from C57BL/6J and DBA/2J mouse lungs to determine aging-related genes

Abstract

This study identified gene expression profiles that provided evidence for genomic mechanisms underlying the pathophysiology of aging lung. Aging lungs from C57BL/6 (B6) and DBA/2 (D2) mouse strains differ in physiology and morphometry. Lungs were harvested from B6 mice at 2, 18, and 26 mo and from D2 mice at 2 and 18 mo of age. Purified RNA was subjected to oligonucleotide microarray analyses, and differential expression analyses were performed for comparison of various data sets. A significant majority of differentially expressed genes were upregulated with aging in both strains. Aging D2 lungs uniquely exhibited upregulation in stress-response genes including xenobiotic detoxification cascades. In contrast, aging B6 lungs showed downregulation of heat shock-response genes. Age-dependent downregulation of genes common to both B6 and D2 strains included several collagen genes (e.g., Col1a1 and Col3a1). There was a greater elastin gene (Eln) expression in D2 mice at 2 mo, and Eln was uniquely downregulated with age in this strain. The matrix metalloproteinase 14 gene (Mmp14), critical to alveolar structural integrity, was also downregulated with aging in D2 mice only. Several polymorphisms in the regulatory and untranslated regions of Mmp14 were identified between strains, suggesting that variation in Mmp14 gene regulation contributes to accelerated aging of lungs in D2 mice. In summary, lungs of B6 and D2 mice age with variable rates at the gene expression level, and these quantifiable genomic differences provide a template for understanding the variability in age-dependent changes in lung structure and function.Mmp14; lung elasticity; lung senescence; microarray; mouse single nucleotide polymorphisms GLOBAL GENE EXPRESSION PROFILING is a powerful tool to generate hypotheses for less understood processes and has been used to study aging-associated gene expression changes in a variety of mouse tissues (8,9,25,27,35,36). However, differential gene expression analyses have not been applied to the aging lung, a critical primary organ in the defense against environmental insults such as airborne pollutants. To date, only one study has documented global expression in healthy human lungs (18) as a function of age. Although this study did not actually achieve statistical significance in gene expression variation with age, modest global differences in gene expression between young and old subjects were observed.The present study offers certain alternatives relative to studies using clinical samples by employing inbred mouse strains. The use of inbred mice achieves several advantages such as isogenicity and genomewide homozygosity among individuals within a strain, which significantly reduces gene expression variability between individuals. This variability was confounding in the aging human study (18). Aging mouse models have been used, for example, to evaluate global gene expression changes in skeletal muscle (35). One of the primary findings with aged skeletal muscle suggested that stress-response genes, including heat...

Hhip haploinsufficiency sensitizes mice to age-related emphysema

“…These age-related impairments in respiratory mechanics were associated with progressively reduced expression of Hhip in Hhip +/+ murine lungs and even greater reductions in Hhip expression in Hhip +/− lungs during aging (Fig. S1) (23), supporting protective roles of Hhip during aging.…”

“…Motivated by human GWAS studies showing that HHIP is associated with both COPD affection status in case-control studies and FEV 1 levels in general population samples (12,13), we demonstrate that HHIP protects aging-related airspace enlargement and increases in lung compliance in mice. Reduction in HHIP expression in COPD lungs (16), as well as in lungs of aging rodents (23), increases susceptibility to develop emphysema during aging. Furthermore, reduced antioxidant capacity and increased oxidant levels in Hhip +/− mice preceded emphysema development.…”

Effects of leptin deficiency on postnatal lung development in mice

“…An absolute fold change (FC) of Ն1.5 was also used as a criterion to select noteworthy genes. These criteria were consistent with the bioinformatics techniques used in previous mouse studies (11,14,31). NetAffx (26) was used to extract gene ontology information for the gene expression profiles.…”

Meta-analysis of gene expression in the mouse liver reveals biomarkers associated with inflammation increased early during aging

“…Aging and longevity studies were also compared to a number of studies which examined gender-dependent gene changes in the mouse liver (Amador-Noguez et al, 2005;Guo et al, 2009). In addition, profiles from aged livers were compared to heart, gastrocnemius muscle and brain neocortex from 30-month versus 5-month-old mice (Barger et al, 2008), lungs from 26-month versus 2-month-old mice (Misra et al, 2007), hematopoietic stem cells from 22 to 23-month versus 2 to 3-month-old mice (Rossi et al, 2005) and brain neocortex from 30-month versus 5-month-old mice (Oberdoerffer et al, 2008). Files (.cel) from all studies and raw gene expression values from the AGEMAP study were uploaded to Rosetta Resolver (Seattle, WA) for analysis.…”

“…The expression of the genes identified in the mouse liver was compared to that in a number of other aging studies. From left to right, these included heart, gastrocnemius muscle and neocortex from 30-month versus 5-month-old mice (Barger et al, 2008), lungs from 26-month versus 2-month-old mice (Misra et al, 2007), hematopoietic stem cells from 22 to 23-month versus 2 to 3-month-old mice (Rossi et al, 2005) and brain neocortex from 30-month versus 5-month-old mice (Oberdoerffer et al, 2008). The genes are presented in the same order as in Fig.…”