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Changes of Ovarian microRNA Profile in Long-Living Ames Dwarf Mice during Aging.

ABSTRACT: The Ames dwarf (df/df) mice have extended longevity and can preserve the ovarian reserve longer than Normal (N) mice. Based on this, the aim of our study was to evaluate the ovarian microRNA (miRNA) profile in young and aged df/df and N mice. Ovarian tissue was collected at 5-6 months and at 21-22 months of age for miRNA sequencing. We detected a total of 404 miRNAs in the ovarian samples, from which the abundance of 22 and 33 miRNAs changed with age in N and df/df mice, respectively. Of these, only three miRNAs were commonly regulated with age between N and df/df mice, indicating a very divergent miRNA profile between genotypes. We also detected that 46 miRNAs were regulated between N and df/df mice, of which 23 were regulated exclusively in young mice, 12 exclusively in old mice and 12 commonly regulated at young and old ages. Many genes likely to be targeted by these miRNAs are involved in the FoxO, mTOR, PI3k/Akt and insulin signaling pathways. These results suggest that the aging process has a differential impact on the ovarian miRNA profile in df/df mice, and suggest that these miRNAs can be central players in the maintenance of a younger ovarian phenotype.

SUBMITTER: Schneider A

PROVIDER: S-EPMC5207734 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Changes of Ovarian microRNA Profile in Long-Living Ames Dwarf Mice during Aging.

Schneider Augusto A Matkovich Scot J SJ Victoria Berta B Spinel Lina L Bartke Andrzej A Golusinski Pawel P Masternak Michal M MM

PloS one 20170103 1

The Ames dwarf (df/df) mice have extended longevity and can preserve the ovarian reserve longer than Normal (N) mice. Based on this, the aim of our study was to evaluate the ovarian microRNA (miRNA) profile in young and aged df/df and N mice. Ovarian tissue was collected at 5-6 months and at 21-22 months of age for miRNA sequencing. We detected a total of 404 miRNAs in the ovarian samples, from which the abundance of 22 and 33 miRNAs changed with age in N and df/df mice, respectively. Of these, ...[more]

PMID: 28046124

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Project description:Long-lived Ames dwarf mice lack growth hormone, prolactin, and thyroid stimulating hormone. Additionally the dwarf mice have enzyme activities and levels that combat oxidative stress more efficiently than those of normal mice. We have shown that methionine metabolism in Ames mice is markedly different than in their wild type littermates. In our previous work we hypothesized that the flux of methionine to the transsulfuration pathway is enhanced in the dwarf mice. The current study was designed to determine whether the flux of methionine to the transsulfuration pathway is increased. We did this by injecting either l-[methyl-(3)H]-methionine or l-[(35)S]-methionine into dwarf or normal mice and then determined retained label (in form of S-adenosylmethionine) 45 min later. The amount of retained hepatic (3)H and (35)S label was significantly reduced in the dwarf mice; at 45 min the specific radioactivity of SAM (pCi/nmol SAM) was 56% lower (p < 0.05) for (3)H-label and 64% lower (p < 0.005) for (35)S-label in dwarf than wild type mice. Retention of (35)S was significantly lower in the brain (37%, p < .04) and kidney (47%, p < 0.02) of the dwarf compared to wild type mice; there was no statistical difference in retained (3)H-label in either brain or kidney. This suggests that both the methyl-moiety and the carbon chain of methionine are lost much faster in the dwarf compared to the wild type mouse, implying that both transmethylation in the liver and transsulfuration in the liver, brain, and kidney are increased in the dwarf mice. As further support, we determined by real-time RT PCR the expression of methionine metabolism genes in livers of mice. Compared to wild type, the Ames dwarf had increased expression of methionine adenosyltransferase 1a (2.3-fold, p = 0.013), glycine N-methyltransferase (3.8-fold, p = 0.023), betaine homocysteine methyltransferase (5.5-fold, p = 0.0006), S-adenosylhomocysteine hydrolase (3.8-fold, p = 0.0005), and cystathionase (2.6-fold; tended to be increased, p = 0.055). Methionine synthase expression was significantly decreased in dwarf compared to wild type (0.48-fold, p = 0.023). These results confirm that the flux of methionine to transsulfuration is enhanced in the Ames dwarf. This, along with data from previous studies support the hypothesis that altered methionine metabolism plays a significant role in the oxidative defense of the dwarf mouse and that the mechanism for the enhanced oxidative defense may be through altered GSH metabolism as a result of the distinctive methionine metabolism.

Project description:BACKGROUND:Extending mammalian health span and life span has been achieved under a variety of dietary restriction protocols. Reducing the intake of a specific amino acid has also been shown to extend health and longevity. We recently reported that methionine (MET) restriction is not effective in life span extension in growth hormone (GH) signaling mutants. To better understand the apparent necessity of GH in the 'sensing' of altered dietary MET, the current study was designed to evaluate MET and glutathione (GSH) metabolism (as well as other pathways) in long-living GH-deficient Ames dwarf and wild-type mice following 8 weeks of restricted (0.16%), low (0.43%), or enriched (1.3%) dietary MET consumption. Metabolite expression was examined in liver tissue, while gene and protein expression were evaluated in liver, kidney, and muscle tissues. RESULTS:Body weight was maintained in dwarf mice on the MET diets, while wild-type mice on higher levels of MET gained weight. Liver MET levels were similar in Ames mice, while several MET pathway enzymes were elevated regardless of dietary MET intake. Transsulfuration enzymes were also elevated in Ames mice but differences in cysteine levels were not different between genotypes. Dwarf mice maintained higher levels of GSH on MET restriction compared to wild-type mice, while genotype and diet effects were also detected in thioredoxin and glutaredoxin. MET restriction increased transmethylation in both genotypes as indicated by increased S-adenosylmethionine (SAM), betaine, and dimethylglycine. Diet did not impact levels of glycolytic components, but dwarf mice exhibited higher levels of key members of this pathway. Coenzyme A and measures of fatty acid oxidation were elevated in dwarf mice and unaffected by diet. CONCLUSIONS:This component analysis between Ames and wild-type mice suggests that the life span differences observed may result from the atypical MET metabolism and downstream effects on multiple systems. The overall lack of responsiveness to the different diets is well reflected across many metabolic pathways in dwarf mice indicating the importance of GH signaling in the ability to discriminate dietary amino acid levels.

Dataset Information

Changes of Ovarian microRNA Profile in Long-Living Ames Dwarf Mice during Aging.

Publications

Changes of Ovarian microRNA Profile in Long-Living Ames Dwarf Mice during Aging.

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