Low Methionine Ingestion by Rats Extends Life Span

Orentreich Foundation for the Advancement of Science, Inc., Biomedical Research Station, Cold Spring-on-Hudson, NY 10516.
Journal of Nutrition (Impact Factor: 3.88). 03/1993; 123(2):269-74.
Source: PubMed


Dietary energy restriction has been a widely used means of experimentally extending mammalian life span. We report here that lifelong reduction in the concentration of a single dietary component, the essential amino acid L-methionine, from 0.86 to 0.17% of the diet results in a 30% longer life span of male Fischer 344 rats. Methionine restriction completely abolished growth, although food intake was actually greater on a body weight basis. Studies of energy consumption in early life indicated that the energy intake of 0.17% methionine-fed animals was near normal for animals of their size, although consumption per animal was below that of the much larger 0.86% methionine-fed rats. Increasing the energy intake of rats fed 0.17% methionine failed to increase their rate of growth, whereas restricting 0.85% methionine-fed rats to the food intake of 0.17% methionine-fed animals did not materially reduce growth, indicating that food restriction was not a factor in life span extension in these experiments. The biochemically well-defined pathways of methionine metabolism and utilization offer the potential for uncovering the precise mechanism(s) underlying this specific dietary restriction-related extension of life span.

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Available from: Jonathan R Matias, Oct 13, 2015
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    • "However, an important distinction between these dietary approaches is that dietary MR does not require restriction of food intake. Quite the contrary, animals on the MR diet develop hyperphagia but paradoxically gain significantly less weight than animals on the control diet [1]. Careful pair-feeding studies showed that dietary MR increased the energy costs of maintaining body weight and decreased the accumulation of fat [4], prima facie evidence that dietary MR impacts energy balance by increasing total energy expenditure (EE). "
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    ABSTRACT: Dietary methionine restriction (MR) produces a coordinated series of biochemical and physiological responses that improve biomarkers of metabolic health, increase energy expenditure, limit fat accretion and improve overall insulin sensitivity. Inguinal white adipose tissue (IWAT) is a primary target and site of action where the diet initiates transcriptional programs linked to enhancing both synthesis and oxidation of lipid. Using a combination of ex vivo approaches to assess dietary effects on cell morphology and function, we report that dietary MR produced a fourfold increase in multilocular, UCP1-expressing cells within this depot in conjunction with significant increases in mitochondrial content, size and cristae density. Dietary MR increased expression of multiple enzymes within the citric acid cycle, as well as respiratory complexes I, II and III. The physiological significance of these responses, evaluated in isolated mitochondria by high-resolution respirometry, was a significant increase in respiratory capacity measured using multiple substrates. The morphological, transcriptional and biochemical remodeling of IWAT mitochondria enhances the synthetic and oxidative capacity of this tissue and collectively underlies its expanded role as a significant contributor to the overall increase in metabolic flexibility and uncoupled respiration produced by the diet. Copyright © 2015. Published by Elsevier Inc.
    The Journal of nutritional biochemistry 08/2015; in press. DOI:10.1016/j.jnutbio.2015.05.016 · 3.79 Impact Factor
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    • "Taken together, the evidence suggests that a significant relationship between plasma GH and MET metabolism exists. Methionine is an essential amino acid in mammals, and restricting MET in the diets of rodents extends lifespan (Orentreich et al., 1993; Miller et al., 2005; Sun et al., 2009). However, excess dietary methionine decreases food intake and growth and induces significant liver pathology (Yalcinkaya et al., 2009). "
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    ABSTRACT: Growth hormone significantly impacts lifespan in mammals. Mouse longevity is extended when growth hormone (GH) signaling is interrupted but markedly shortened with high-plasma hormone levels. Methionine metabolism is enhanced in growth hormone deficiency, for example, in the Ames dwarf, but suppressed in GH transgenic mice. Methionine intake affects also lifespan, and thus, GH mutant mice and respective wild-type littermates were fed 0.16%, 0.43%, or 1.3% methionine to evaluate the interaction between hormone status and methionine. All wild-type and GH transgenic mice lived longer when fed 0.16% methionine but not when fed higher levels. In contrast, animals without growth hormone signaling due to hormone deficiency or resistance did not respond to altered levels of methionine in terms of lifespan, body weight, or food consumption. Taken together, our results suggest that the presence of growth hormone is necessary to sense dietary methionine changes, thus strongly linking growth and lifespan to amino acid availability.
    Aging cell 09/2014; 13(6). DOI:10.1111/acel.12269 · 6.34 Impact Factor
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    • "Methionine restriction (MR) is a dietary technique, with the only manipulation of the diet being a reduction in the essential amino acid methionine (from 0.86% of the diet to 0.172%). Methionine restriction has been shown previously to extend lifespan (Orentreich et al., 1993; Richie et al., 1994), dramatically decrease body weight and adiposity, and improve insulin sensitivity relative to animals on a control diet (Hasek et al., 2010; Plaisance et al., 2010; Ables et al., 2012). Methionine restriction has, therefore, been proposed to mimic effects of caloric restriction (CR) (Masoro, 2005); however, in contrast to CR, animals on MR diet are fed ad libitum and actually consume more food than control-fed animals (Hasek et al., 2010; Plaisance et al., 2010). "
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    ABSTRACT: Methionine restriction (MR) decreases body weight and adiposity and improves glucose homeostasis in rodents. Similar to caloric restriction, MR extends lifespan, but is accompanied by increased food intake and energy expenditure. Most studies have examined MR in young animals; therefore, the aim of this study was to investigate the ability of MR to reverse age-induced obesity and insulin resistance in adult animals. Male C57BL/6J mice aged 2 and 12 months old were fed MR (0.172% methionine) or control diet (0.86% methionine) for 8 weeks or 48 h. Food intake and whole-body physiology were assessed and serum/tissues analyzed biochemically. Methionine restriction in 12-month-old mice completely reversed age-induced alterations in body weight, adiposity, physical activity, and glucose tolerance to the levels measured in healthy 2-month-old control-fed mice. This was despite a significant increase in food intake in 12-month-old MR-fed mice. Methionine restriction decreased hepatic lipogenic gene expression and caused a remodeling of lipid metabolism in white adipose tissue, alongside increased insulin-induced phosphorylation of the insulin receptor (IR) and Akt in peripheral tissues. Mice restricted of methionine exhibited increased circulating and hepatic gene expression levels of FGF21, phosphorylation of eIF2a, and expression of ATF4, with a concomitant decrease in IRE1α phosphorylation. Short-term 48-h MR treatment increased hepatic FGF21 expression/secretion and insulin signaling and improved whole-body glucose homeostasis without affecting body weight. Our findings suggest that MR feeding can reverse the negative effects of aging on body mass, adiposity, and insulin resistance through an FGF21 mechanism. These findings implicate MR dietary intervention as a viable therapy for age-induced metabolic syndrome in adult humans.
    Aging cell 06/2014; 13(5). DOI:10.1111/acel.12238 · 6.34 Impact Factor
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