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Short-term calorie restriction in male mice feminizes gene expression and alters key regulators of conserved aging regulatory pathways.

Estep PW, Warner JB, Bulyk ML - PLoS ONE (2009)

Bottom Line: CR generally feminizes gene expression and many of the most significantly changed individual genes are involved in aging, hormone signaling, and p53-associated regulation of the cell cycle and apoptosis.Using western analysis we confirmed post-translational inhibition of the TOR pathway.Our data show that CR induces widespread gene expression changes and acts through highly evolutionarily conserved pathways, from microorganisms to mammals, and that its life-extension effects might arise partly from a shift toward a gene expression profile more typical of females.

View Article: PubMed Central - PubMed

Affiliation: Longenity Inc, Lincoln, MA, USA. pestep@post.harvard.edu

ABSTRACT

Background: Calorie restriction (CR) is the only intervention known to extend lifespan in a wide range of organisms, including mammals. However, the mechanisms by which it regulates mammalian aging remain largely unknown, and the involvement of the TOR and sirtuin pathways (which regulate aging in simpler organisms) remain controversial. Additionally, females of most mammals appear to live longer than males within species; and, although it remains unclear whether this holds true for mice, the relationship between sex-biased and CR-induced gene expression remains largely unexplored.

Methodology/principal findings: We generated microarray gene expression data from livers of male mice fed high calorie or CR diets, and we find that CR significantly changes the expression of over 3,000 genes, many between 10- and 50-fold. We compare our data to the GenAge database of known aging-related genes and to prior microarray expression data of genes expressed differently between male and female mice. CR generally feminizes gene expression and many of the most significantly changed individual genes are involved in aging, hormone signaling, and p53-associated regulation of the cell cycle and apoptosis. Among the genes showing the largest and most statistically significant CR-induced expression differences are Ddit4, a key regulator of the TOR pathway, and Nnmt, a regulator of lifespan linked to the sirtuin pathway. Using western analysis we confirmed post-translational inhibition of the TOR pathway.

Conclusions: Our data show that CR induces widespread gene expression changes and acts through highly evolutionarily conserved pathways, from microorganisms to mammals, and that its life-extension effects might arise partly from a shift toward a gene expression profile more typical of females.

Show MeSH
GO categories with largest relative fractions of upregulated or downregulated genes.Each stacked bar graph displays the relative upregulated or downregulated fractions of the total number of genes (n = 100%) significantly altered by CR within a given GO category returned by FuncAssociate (adjusted p<0.05). The upregulated fraction is shown in red and the downregulated fraction is shown in blue.
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pone-0005242-g003: GO categories with largest relative fractions of upregulated or downregulated genes.Each stacked bar graph displays the relative upregulated or downregulated fractions of the total number of genes (n = 100%) significantly altered by CR within a given GO category returned by FuncAssociate (adjusted p<0.05). The upregulated fraction is shown in red and the downregulated fraction is shown in blue.

Mentions: To more clearly understand the changes in biological function that result from changes in gene expression, for each GO term we plotted in a stacked bar graph the relative fraction of upregulated and downregulated genes associated with that GO term from the SAM output (q<0.1). Figure 3 shows a selection (culled to eliminate excessive redundancy) of the GO terms with the largest fractions of upregulated or downregulated genes. CR results in a clear relative upregulation of genes involved in protein biosynthesis, rRNA processing, mRNA metabolism and splicing, ribosome, and regulation of protein translation. Many GO categories consist mostly of downregulated genes including those involved in mitochondria, carboxylic acid metabolism, DNA replication, steroid, cholesterol and lipid metabolism, lysosome, peroxisome, and glutathione S-transferase activity. Several downregulated GO classes are involved in protein turnover including endoplasmic reticulum/ER, isomerase activity, amino acid derivative biosynthesis, protein positioning, and the proteasome.


Short-term calorie restriction in male mice feminizes gene expression and alters key regulators of conserved aging regulatory pathways.

Estep PW, Warner JB, Bulyk ML - PLoS ONE (2009)

GO categories with largest relative fractions of upregulated or downregulated genes.Each stacked bar graph displays the relative upregulated or downregulated fractions of the total number of genes (n = 100%) significantly altered by CR within a given GO category returned by FuncAssociate (adjusted p<0.05). The upregulated fraction is shown in red and the downregulated fraction is shown in blue.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2667255&req=5

pone-0005242-g003: GO categories with largest relative fractions of upregulated or downregulated genes.Each stacked bar graph displays the relative upregulated or downregulated fractions of the total number of genes (n = 100%) significantly altered by CR within a given GO category returned by FuncAssociate (adjusted p<0.05). The upregulated fraction is shown in red and the downregulated fraction is shown in blue.
Mentions: To more clearly understand the changes in biological function that result from changes in gene expression, for each GO term we plotted in a stacked bar graph the relative fraction of upregulated and downregulated genes associated with that GO term from the SAM output (q<0.1). Figure 3 shows a selection (culled to eliminate excessive redundancy) of the GO terms with the largest fractions of upregulated or downregulated genes. CR results in a clear relative upregulation of genes involved in protein biosynthesis, rRNA processing, mRNA metabolism and splicing, ribosome, and regulation of protein translation. Many GO categories consist mostly of downregulated genes including those involved in mitochondria, carboxylic acid metabolism, DNA replication, steroid, cholesterol and lipid metabolism, lysosome, peroxisome, and glutathione S-transferase activity. Several downregulated GO classes are involved in protein turnover including endoplasmic reticulum/ER, isomerase activity, amino acid derivative biosynthesis, protein positioning, and the proteasome.

Bottom Line: CR generally feminizes gene expression and many of the most significantly changed individual genes are involved in aging, hormone signaling, and p53-associated regulation of the cell cycle and apoptosis.Using western analysis we confirmed post-translational inhibition of the TOR pathway.Our data show that CR induces widespread gene expression changes and acts through highly evolutionarily conserved pathways, from microorganisms to mammals, and that its life-extension effects might arise partly from a shift toward a gene expression profile more typical of females.

View Article: PubMed Central - PubMed

Affiliation: Longenity Inc, Lincoln, MA, USA. pestep@post.harvard.edu

ABSTRACT

Background: Calorie restriction (CR) is the only intervention known to extend lifespan in a wide range of organisms, including mammals. However, the mechanisms by which it regulates mammalian aging remain largely unknown, and the involvement of the TOR and sirtuin pathways (which regulate aging in simpler organisms) remain controversial. Additionally, females of most mammals appear to live longer than males within species; and, although it remains unclear whether this holds true for mice, the relationship between sex-biased and CR-induced gene expression remains largely unexplored.

Methodology/principal findings: We generated microarray gene expression data from livers of male mice fed high calorie or CR diets, and we find that CR significantly changes the expression of over 3,000 genes, many between 10- and 50-fold. We compare our data to the GenAge database of known aging-related genes and to prior microarray expression data of genes expressed differently between male and female mice. CR generally feminizes gene expression and many of the most significantly changed individual genes are involved in aging, hormone signaling, and p53-associated regulation of the cell cycle and apoptosis. Among the genes showing the largest and most statistically significant CR-induced expression differences are Ddit4, a key regulator of the TOR pathway, and Nnmt, a regulator of lifespan linked to the sirtuin pathway. Using western analysis we confirmed post-translational inhibition of the TOR pathway.

Conclusions: Our data show that CR induces widespread gene expression changes and acts through highly evolutionarily conserved pathways, from microorganisms to mammals, and that its life-extension effects might arise partly from a shift toward a gene expression profile more typical of females.

Show MeSH