cDNA expression arrays reveal incomplete reversal of age-related changes in gene expression by calorie restriction

Han, Eun Soo; Hilsenbeck, Susan G.; Richardson, Arlan; Nelson, James F.

doi:10.1016/s0047-6374(00)00119-6

Cited by 49 publications

(24 citation statements)

References 41 publications

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“…Physiol Genomics • VOL 15 • www.physiolgenomics.org (16,21,23,28). However, the present study differs from these reports in that the number of genes whose expression increases with age outnumbers those decreasing by greater than twofold.…”

Section: Transcript Profiling In Aged Heartscontrasting

confidence: 91%

“…The current study is in agreement with these previous reports in that aging is not associated with widespread alterations in gene expression. Estimates of the number of genes that exhibit differential gene expression range from 1 to 4% of the total number of genes queried (16,21,28,29). With the exception of the analysis of cultured cells, aging is not associated with an overall decrease in gene expression, because liver, brain, and skeletal muscle studies reveal that a near equal numbers of transcripts are up-or downregulated with aging Fig.…”

Section: Discussionmentioning

confidence: 99%

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Molecular mechanisms of reduced β-adrenergic signaling in the aged heart as revealed by genomic profiling

Dobson

Fray

Leonard

et al. 2003

Physiological Genomics

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.-Myocardial aging leads to a reduction of ␤-adrenergic receptor-induced metabolic and contractile responsiveness. We hypothesize that a change in the patterns of gene expression is important in these age-related events. To test this, hearts were harvested from young and aged male rats (3-4 and 20-22 mo, respectively). Total mRNA was extracted and prepared for hybridization to Affymetrix U34A GeneChips. Filtering criteria, involving fold change and a statistical significance cutoff were employed, yielding 263 probe pairs exhibiting differential signals. Of the 163 annotated genes, at least 56 (34%) were classified as signaling/cell communication. Of these 56, approximately half were directly involved in G protein-coupled receptor signaling pathways. We next determined which of these changes might be involved in anti-adrenergic activity and identified 19 potentially important gene products. Importantly, we observed a decrease in ␤1-adrenergic receptor and adenylyl cyclase mRNAs, whereas the mRNA encoding ␤-arrestin increased. Furthermore, the results demonstrate an increase in mRNAs encoding the adenosine A1 receptor and phospholipase D, which could increase anti-adrenergic effects. Moreover, the mRNAs encoding the muscarinic M3 receptor, nicotinic acetylcholine receptor ␤3, and nicotinic acetylcholine receptor-related protein were increased as was the mRNA encoding guanylate kinase-associated protein. Interestingly, we also observed eight mRNAs whose abundance changed three-to sixfold with aging that could be considered as being compensatory. Although these results do not prove causality, they demonstrate that cardiac aging is associated with changes in the profiles of gene expression and that many of these changes may contribute to reduced adrenergic signaling. gene expression; aging; anti-adrenergic; G protein-coupled receptors; physiological genomics THE ABILITY OF THE HEART to respond to excitatory signaling cues is the dominant regulator of cardiac function. The hallmark of the aged heart is an impairment of the excitatory response to ␤-adrenergic agonists leading to a deficit in cardiac contractility and metabolism (26,27). The ␤-adrenergic signaling system also plays a central role in the pathophysiology of congestive heart failure (17). Despite the importance of this system, the factors that contribute to a decreased responsiveness in signaling, particularly with aging, are unclear.The ␤-adrenergic signaling cascade is composed of membrane receptors, signal transducers, and downstream effector molecules. The receptor-signaling cascade is dynamically regulated by the phosphorylation state catalyzed by common and pathway-specific enzymes. Although the individual candidate approach has provided some clues as to the changes that occur with aging, the basic premise guiding these studies is that the determinants of ␤-adrenergic responsiveness will be few and the regulatory circuits will be simple. However, it is clear that the signaling pathways for membrane receptors are not simple but are highly integrated a...

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Section: Transcript Profiling In Aged Heartscontrasting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms of reduced β-adrenergic signaling in the aged heart as revealed by genomic profiling

Dobson

Fray

Leonard

et al. 2003

Physiological Genomics

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“…The F 2 mice utilized for our microarray study were much older (16 mo) than the F 1 mice (10-12 wk), and the F 2 mice had been on a high-fat, atherogenic diet for 16 wk prior to profiling the livers compared with the F 1 mice that were on a standard chow diet. These differences could conceivably have an effect on gene expression (Han et al 2000;Jaenisch and Bird 2003;Sharman et al 2004), invoking trans effects in the F 1 mice, which in some cases override the cis effects of the locus of interest, thereby bringing the allelic expression ratio closer to 1:1.…”

Section: Validation Of Cis-regulated Genesmentioning

confidence: 99%

Cis-acting expression quantitative trait loci in mice

Doss¹,

Schadt²,

Drake³

et al. 2005

Genome Res.

252

249

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We previously reported the analysis of genome-wide expression profiles and various diabetes-related traits in a segregating cross between inbred mouse strains C57BL/6J (B6) and DBA/2J (DBA). By considering transcript levels as quantitative traits, we identified several thousand expression quantitative trait loci (eQTL) with LOD score >4.3. We now experimentally address the problem of multiple comparisons by estimating the fraction of false-positive eQTL that are under cis-acting regulation. For this, we have utilized a classic cis-trans test with (B6 × DBA)F 1 mice to determine the relative levels of transcripts from the B6 and DBA alleles. The results suggest that at least 64% of cis-acting eQTL with LOD >4.3 are true positives, while the remaining 36% could not be confirmed as truly cis-acting. Moreover, we find that >96% of apparent cis-acting eQTL occur in regions that do not share SNP haplotypes. Cis-acting eQTL serve as an important new resource for the identification of positional candidates in QTL studies in mice. Also, we use the analysis of the correlation structures between genotypes, gene expression traits, and phenotypic traits to further characterize genes expressed in liver that are under cis-acting control, and highlight the advantages and disadvantages of integrating genetics and gene expression data in segregating populations.

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“…Similar studies at the tissue and organ level, however, have proven difficult due to the heterogeneous nature of the specimens. To date, tissue profiling of the aging process has been confined mainly to DNA microarray analysis of mouse and human muscle (19 -21) and mouse brain (22,23) and liver (24,25). In general, these studies have shown that the expression of only a small fraction of the genes analyzed changed during the aging process.…”

Section: Molecular and Cellular Proteomics 2:70 -84 2003mentioning

confidence: 99%

Protein Profiling of the Human Epidermis from the Elderly Reveals Up-regulation of a Signature of Interferon-γ-induced Polypeptides That Includes Manganese-superoxide Dismutase and the p85β Subunit of Phosphatidylinositol 3-Kinase

Gromov

Skovgaard

Pálsdóttir

et al. 2003

Molecular & Cellular Proteomics

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cDNA expression arrays reveal incomplete reversal of age-related changes in gene expression by calorie restriction

Cited by 49 publications

References 41 publications

Molecular mechanisms of reduced β-adrenergic signaling in the aged heart as revealed by genomic profiling

Molecular mechanisms of reduced β-adrenergic signaling in the aged heart as revealed by genomic profiling

Cis-acting expression quantitative trait loci in mice

Protein Profiling of the Human Epidermis from the Elderly Reveals Up-regulation of a Signature of Interferon-γ-induced Polypeptides That Includes Manganese-superoxide Dismutase and the p85β Subunit of Phosphatidylinositol 3-Kinase

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