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

Abstract

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.

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

“…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.…”

The Mitochondrial Free Radical Theory of Aging

“…72 Also in agreement with a methionine role in aging, it has been reported that long-lived Ames dwarf mice have an altered methionine metabolism showing a marked increase in the transulfuration pathway compared to their wild-type siblings. 73 All the above results point to methionine as the single dietary factor responsible for part of the longevity extension effect of DR.…”

Betaine homocysteine S-methyltransferase: just a regulator of homocysteine metabolism?

“…However, to date, most of the data available on BHMT regulation come from early studies on the effects exerted in the whole methionine cycle by several hormonal treatments. Increases in BHMT activity and mRNA levels were observed by the action of hydrocortisone, cortisol and triamcinolone, whereas growth hormone only induced BHMT mRNA [18,34,65,[70][71][72][73][74][75][76].…”