Growth hormone alters methionine and glutathione metabolism in Ames dwarf mice

Brown‐Borg, Holly M.; Rakoczy, Sharlene; Uthus, Eric O.

doi:10.1016/j.mad.2004.09.005

Cited by 63 publications

(55 citation statements)

References 54 publications

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“…However, the assay we used in our original paper did not differentiate between Mat I and III or, if expressed in the mouse livers, Mat II. Our research showed that liver Mat was increased 205% in the dwarf compared to wild type mouse and that GH administration to dwarf mice results in an approximate 40% suppression of Mat activity (Uthus and Brown-Borg, 2003;Brown-Borg et al, 2005). We now show that mRNA expression of Mat1a was increased 2.3-fold; Mat 2a was not different between dwarf and wild type.…”

Section: Discussionmentioning

confidence: 54%

“…Because Gnmt is a major enzyme in liver making up between 0.5 and 1% of the soluble protein in rat liver cytosol (Wagner et al, 1985), it is likely that the changes seen in Gnmt (91% increase in activity and 3.8-fold increase in mRNA) are of physiological significance. In addition, we have shown that GH administration to dwarf mice results in an approximate 44% decrease in activity of hepatic Gnmt (Brown-Borg et al, 2005). Thus, in the Ames dwarf mouse which lacks GH, the concomitant increase in Gnmt activity and expression results in a decrease in the pool size of SAM and an increase in SAH concentration.…”

Section: Discussionmentioning

confidence: 82%

“…Ames dwarf mice live 50-64% longer than their wild type littermates (males and females, respectively) (Brown-Borg et al, 2005) and these mice have a delayed occurrence and reduced incidence of presumably fatal neoplastic disease compared with their normal siblings (Ikeno et al, 2003). Ames dwarf mice have a homozygous recessive mutation at the Prop-1 locus, which leads to a lack of differentiation of somatotrophic, lactotrophic, and thyrotrophic pituitary cells.…”

Section: Introductionmentioning

confidence: 99%

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Methionine flux to transsulfuration is enhanced in the long living Ames dwarf mouse

Uthus

Brown‐Borg

2006

Mechanisms of Ageing and Development

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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 < 0.04) 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.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

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Methionine flux to transsulfuration is enhanced in the long living Ames dwarf mouse

Uthus

Brown‐Borg

2006

Mechanisms of Ageing and Development

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“…The strongest evidence comes from studies in rats and mice in which amino acids are fed in lieu of protein, where restriction of dietary methionine alone can extend maximum lifespan by 10-45% (Orentreich et al 1993;Richie et al 1994;Zimmerman et al 2003;Miller et al 2005). Methionine metabolism is abnormal in long-lived mutant mice that are deficient in growth hormone, prolactin and thyroid stimulating hormone (Uthus and Brown-Borg 2003;Brown-Borg et al 2005;Uthus and Brown-Borg 2006). Furthermore, methionine restriction specifically inhibits the induction of IGF-I expression by growth hormone in pig hepatocytes (Stubbs et al 2002), indicating a potential regulatory interaction of methionine metabolism on the growth hormone-IGF-I signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Lifespan modification by glucose and methionine in Drosophila melanogaster fed a chemically defined diet

Troen

French

Roberts

et al. 2006

AGE

105

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Experimentally restricting dietary calories, while maintaining adequate dietary nutrient content, extends lifespan in phylogenetically diverse species; thus suggesting the existence of conserved pathways which can modify lifespan in response to energy intake. However, in some cases the impact on longevity may depend on the quality of the energy source. In Drosophila, restriction of dietary yeast yields considerable lifespan extension whereas isocaloric restriction of dietary sugar yields only modest extension, indicating that other diet-responsive pathways can modify lifespan in this species. In rodents, restricting intake of a single amino acid -methionine -extends lifespan. Here we show that dietary methionine can modify lifespan in adult female, non-virgin Oregon-R strain Drosophila fed a chemically defined media. Compared to a diet containing 0.135% methionine and 15% glucose, high dietary methionine (0.405%) shortened maximum lifespan by 2.33% from 86 to 84 days and mean lifespan by 9.55% from 71.7 to 64.9 days. Further restriction of methionine to 0.045% did not extend maximum lifespan and shortened mean lifespan by 1.95% from 71.1 to 70.3 days. Restricting glucose from 15% to 5% while holding methionine at a concentration of 0.135%, modestly extended maximum lifespan by 5.8% from 86 to 91 days, without extending mean lifespan. All these diet-induced changes were highly significant (log-rank p<0.0001). Notably, all four diets resulted in considerably longer life spans than those typically reported for flies fed conventional yeast and sugar based diets. Such defined diets can be used to identify lifespan-modifying pathways and specific gene-nutrient interactions in Drosophila.

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“…Metallothionein and glutathione both exhibit ROS scavenging abilities, and levels of these are significantly increased in multiple tissues from the dwarf mouse (Meyer et al, 2003;Brown-Borg et al, 2001). The amino acid methionine, whose metabolic pathway feeds cysteine residues into the GSH pathway, is also highly upregulated in the Ames mouse (Brown-Borg et al, 2005;Uthus and Brown-Borg, 2003;.…”

Section: Growth Hormone/insulin-like Growth Factor 1/insulinmentioning

confidence: 99%

Hormonal regulation of longevity in mammals

Brown‐Borg

2007

Ageing Research Reviews

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Multiple biological and environmental factors impact the life span of an organism. The endocrine system is a highly integrated physiological system in mammals that regulates metabolism, growth, reproduction, and response to stress, among other functions. As such, this pervasive entity has a major influence on aging and longevity. The growth hormone, insulin-like growth factor-1 and insulin pathways have been at the forefront of hormonal control of aging research in the last few years. Other hormones, including those from the thyroid and reproductive system have also been studied in terms of life span regulation. The relevance of these hormones to human longevity remains to be established, however the evidence from other species including yeast, nematodes, and flies suggest that evolutionarily well-conserved mechanisms are at play and the endocrine system is a key determinant.

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Growth hormone alters methionine and glutathione metabolism in Ames dwarf mice

Cited by 63 publications

References 54 publications

Methionine flux to transsulfuration is enhanced in the long living Ames dwarf mouse

Methionine flux to transsulfuration is enhanced in the long living Ames dwarf mouse

Lifespan modification by glucose and methionine in Drosophila melanogaster fed a chemically defined diet

Hormonal regulation of longevity in mammals

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