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Mitochondrial gene expression decline in aging is tissue-specific and independent of mitochondrial number

ABSTRACT: Aging is the progressive decline in organismal function that leads to an increased risk of multiple diseases and mortality. The molecular basis of this decline is unknown. Using quantitative PCR for mitochondrial mRNA from multiple tissues from the same animals, we found that the rate of change in mouse mitochondrial expression is tissue-specific, with cardiac expression declining early (8-10 months), adipose expression declining late (25-30 months), and no change in kidney or skin. In cardiac tissue, mitochondria-derived mRNA levels declined more slowly than nuclear encoded mRNAs, suggesting a potential dysregulation. These changes were independent of alteration in mitochondrial number, as measured by quantitative PCR of mitochondrial DNA and citrate synthase activity. We found no change in the variability between mitochondrial mRNA levels with age, suggesting that the changes are not due to random dysregulation at the level of gene expression. Caloric restriction (CR), a lifespan-extending intervention proposed to act through mitochondrial biogenesis, delayed the decline in both cardiac and adipose mitochondrial mRNA levels of F344 rats. CR caused an increase in citrate synthase activity but did not alter mitochondrial DNA content, indicating increased translation or reduced turnover of mitochondrial proteins. These results demonstrate that mitochondrial gene expression changes with age are not coupled to mitochondrial number, are likely to be regulated, and are governed by tissue-specific processes. These findings indicate that aging is neither a programmed organism-wide change orchestrated in a top-down fashion nor a product of random dysregulation of gene expression but that tissue-specific factors may independently control aging in different organ compartments. Keywords: aging

ORGANISM(S): Mus musculus

PROVIDER: GSE12480 | GEO | 2015/07/03

SECONDARY ACCESSION(S): PRJNA112957

REPOSITORIES: GEO

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Project description:Sustained caloric restriction (CR) extends lifespan in animal models but the mechanism and primary tissue target(s) have not been identified. Gene expression changes with aging and CR were examined in both heart and subcutaneous white adipose tissue (WAT) of F344 male rats using AffymetrixÂ® RAE 230 arrays and validated by qRT-PCR on 18 genes. In heart, age- associated changes but not CR-associated changes in old. In WAT, genes were identified where the aging change is suppressed by CR (candidate markers of healthy aging) and those affected by CR but not normal aging (candidate longevity assurance genes). 10-21% of age-associated genes were regulated in common between tissues. Gene set enrichment analysis (GSEA) revealed coordinate small magnitude changes in ribosomal, proteasomal, and mitochondrial genes with similarities between heart and WAT. Further analysis revealed PPARgamma as a potential upstream regulator of altered gene expression in old CR WAT. These results demonstrate a reduced mRNA response to CR with age in heart relative to WAT. In WAT, we identified candidate CR mimetic targets and candidate markers of healthy aging. These data suggest a role for subcutaneous WAT in the effects of CR and strengthen the role for PPAR signaling in aging and CR while indicating that the effects of CR in heart can occur independent of global changes in mRNA level. Experiment Overall Design: Tissues (n=5-7 animals per group) were obtained from the NIH-NIA aging rodent tissue bank. According to supplier records, animals were housed in a specific pathogen free barrier facility under contract with BioReliance. AL animals were housed 3 per cage and CR animals were housed singly. CR (60% of AL) was initiated at 4 months of age with a switch from the NIH 31 to NIH fortified diet. F344 male rats were sacrificed at 4 months (4AL) or 28 months of age (28AL, 28CR). Animals with gross tumor pathologies were excluded from the study. All animals were euthanized by CO2 asphixiation and tissues were frozen in liquid nitrogen then stored at â80Â°C. Subcutaneous WAT was collected from the abdominal region. Recorded body weights differed dramatically between the 3 groups (4AL = 253Â±8 g, 28AL = 382Â±20 g, 28CR = 288Â±7 g) and heart weight as a fraction of body weight was not significantly different between the groups (data not shown). The apical ~1/3 of the heart was homogenized for the expression studies. Sections from the cut face were stained with haematoxylin and eosin to confirm expected aging-associated pathology changes.

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Mitochondrial gene expression decline in aging is tissue-specific and independent of mitochondrial number

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