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Caloric restriction counteracts age-dependent changes in prolyl-4-hydroxylase domain (PHD) 3 expression.

Rohrbach S, Teichert S, Niemann B, Franke C, Katschinski DM - Biogerontology (2008)

Bottom Line: Previously, we have described an elevated expression of the prolyl-4-hydroxylase domain (PHD) 3 with increasing age in mouse and human heart.In the present study we demonstrate that elevated PHD3, but not PHD1 or PHD2, expression is not restricted to the heart but does also occur in rat skeletal muscle and liver.Age-associated changes in PHD3 expression inversely correlated with the expression of the HIF-target gene macrophage migration inhibitory factor (MIF), which has been previously described to be involved in cellular HIF-mediated anti-ageing effects.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathophysiology, Martin-Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06112 Halle, Germany.

ABSTRACT
Caloric restriction remains the most reproducible measure known to extend life span or diminish age-associated changes. Previously, we have described an elevated expression of the prolyl-4-hydroxylase domain (PHD) 3 with increasing age in mouse and human heart. PHDs modulate the cellular response towards hypoxia by regulating the stability of the alpha-subunit of the transcriptional activator hypoxia inducible factor (HIF). In the present study we demonstrate that elevated PHD3, but not PHD1 or PHD2, expression is not restricted to the heart but does also occur in rat skeletal muscle and liver. Elevated expression of PHD3 is counteracted by a decrease in caloric intake (40% caloric restriction applied for 6 months) in all three tissues. Age-associated changes in PHD3 expression inversely correlated with the expression of the HIF-target gene macrophage migration inhibitory factor (MIF), which has been previously described to be involved in cellular HIF-mediated anti-ageing effects. These data give insight into the molecular consequences of caloric restriction, which influences hypoxia-mediated gene expression via PHD3.

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Effect of age and caloric restriction on MIF mRNA expression. Tissue samples (heart, liver and skeletal muscle (M. gastrocnemicus)) were obtained from young (6 months old) and old (24 months old) rats with or without a 40% caloric restriction applied for 6 months. Subsequently, RNA was extracted and MIF mRNA quantitated by real time PCR
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Fig4: Effect of age and caloric restriction on MIF mRNA expression. Tissue samples (heart, liver and skeletal muscle (M. gastrocnemicus)) were obtained from young (6 months old) and old (24 months old) rats with or without a 40% caloric restriction applied for 6 months. Subsequently, RNA was extracted and MIF mRNA quantitated by real time PCR

Mentions: Numerous HIF-target genes, including erythropoietin, vascular endothelial growth factor, carbonic anhydrase IX etc., have been identified (Wenger et al. 2005). Recently, the expression of the macrophage migration inhibitory factor (MIF) has been demonstrated to be inducible by hypoxia. In addition, functional HIF binding sites in the promoter have been identified. In a recent study evidence was provided that HIF-1 plays a critical role in delaying the onset of senescence in rodent cells via transcriptional activation of MIF and thereby inhibition of the p53-mediated pathway (Welford et al. 2006). To gain insight into the functional consequences of age and caloric restriction-mediated changes on the HIF-induced signal transduction pathways, we analyzed the mRNA expression of MIF as a function of age and caloric restriction. In line with the suggestion that HIF-dependent gene expression is hampered with increasing age, MIF RNA and protein expression was significantly lower in the heart, liver and skeletal muscle obtained from the old rats compared to the expression found in the young rats (Figs. 4, 5). Restriction of food intake reversed the age-dependent decline in MIF expression (Fig. 4). MIF levels after caloric restriction were comparable to the expression levels in young rats in all three tissues investigated.Fig. 4


Caloric restriction counteracts age-dependent changes in prolyl-4-hydroxylase domain (PHD) 3 expression.

Rohrbach S, Teichert S, Niemann B, Franke C, Katschinski DM - Biogerontology (2008)

Effect of age and caloric restriction on MIF mRNA expression. Tissue samples (heart, liver and skeletal muscle (M. gastrocnemicus)) were obtained from young (6 months old) and old (24 months old) rats with or without a 40% caloric restriction applied for 6 months. Subsequently, RNA was extracted and MIF mRNA quantitated by real time PCR
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2367389&req=5

Fig4: Effect of age and caloric restriction on MIF mRNA expression. Tissue samples (heart, liver and skeletal muscle (M. gastrocnemicus)) were obtained from young (6 months old) and old (24 months old) rats with or without a 40% caloric restriction applied for 6 months. Subsequently, RNA was extracted and MIF mRNA quantitated by real time PCR
Mentions: Numerous HIF-target genes, including erythropoietin, vascular endothelial growth factor, carbonic anhydrase IX etc., have been identified (Wenger et al. 2005). Recently, the expression of the macrophage migration inhibitory factor (MIF) has been demonstrated to be inducible by hypoxia. In addition, functional HIF binding sites in the promoter have been identified. In a recent study evidence was provided that HIF-1 plays a critical role in delaying the onset of senescence in rodent cells via transcriptional activation of MIF and thereby inhibition of the p53-mediated pathway (Welford et al. 2006). To gain insight into the functional consequences of age and caloric restriction-mediated changes on the HIF-induced signal transduction pathways, we analyzed the mRNA expression of MIF as a function of age and caloric restriction. In line with the suggestion that HIF-dependent gene expression is hampered with increasing age, MIF RNA and protein expression was significantly lower in the heart, liver and skeletal muscle obtained from the old rats compared to the expression found in the young rats (Figs. 4, 5). Restriction of food intake reversed the age-dependent decline in MIF expression (Fig. 4). MIF levels after caloric restriction were comparable to the expression levels in young rats in all three tissues investigated.Fig. 4

Bottom Line: Previously, we have described an elevated expression of the prolyl-4-hydroxylase domain (PHD) 3 with increasing age in mouse and human heart.In the present study we demonstrate that elevated PHD3, but not PHD1 or PHD2, expression is not restricted to the heart but does also occur in rat skeletal muscle and liver.Age-associated changes in PHD3 expression inversely correlated with the expression of the HIF-target gene macrophage migration inhibitory factor (MIF), which has been previously described to be involved in cellular HIF-mediated anti-ageing effects.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathophysiology, Martin-Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06112 Halle, Germany.

ABSTRACT
Caloric restriction remains the most reproducible measure known to extend life span or diminish age-associated changes. Previously, we have described an elevated expression of the prolyl-4-hydroxylase domain (PHD) 3 with increasing age in mouse and human heart. PHDs modulate the cellular response towards hypoxia by regulating the stability of the alpha-subunit of the transcriptional activator hypoxia inducible factor (HIF). In the present study we demonstrate that elevated PHD3, but not PHD1 or PHD2, expression is not restricted to the heart but does also occur in rat skeletal muscle and liver. Elevated expression of PHD3 is counteracted by a decrease in caloric intake (40% caloric restriction applied for 6 months) in all three tissues. Age-associated changes in PHD3 expression inversely correlated with the expression of the HIF-target gene macrophage migration inhibitory factor (MIF), which has been previously described to be involved in cellular HIF-mediated anti-ageing effects. These data give insight into the molecular consequences of caloric restriction, which influences hypoxia-mediated gene expression via PHD3.

Show MeSH
Related in: MedlinePlus