Lifelong dietary methionine restriction (MR) is associated with increased longevity and decreased incidence of age-related disorders and diseases in rats and mice. A reduction in the levels of oxidative stress may be a contributing mechanistic factor for the beneficial effects of MR. To examine this, we determined the effects of an 80% dietary restriction of Met on different biomarkers of oxidative stress and antioxidant pathways in blood, liver, kidney and brain in the rat. Male F-344 rats were fed control (0.86% methionine) or MR (0.17% methionine) diets for up to six months. Blood and tissues were analyzed for glutathione (GSH) concentrations, related enzyme activities and biomarkers of oxidative stress. MR was associated with reductions in oxidative stress biomarkers including plasma 8-hydoxydeoxyguanosine (8-OHdG) and 8-isoprostane and erythrocyte protein-bound glutathione after one month with levels remaining low for at least six months (P < 0.05). Levels of free GSH in blood were increased after 1–6 months of MR feeding whereas liver GSH levels were reduced over this time (P < 0.05). In MR rats, GSH peroxidase activity was decreased in liver and increased in kidney compared with controls. No changes in the activities of GSH reductase in liver and kidney and superoxide dismutase in liver were observed as a result of MR feeding. Altogether, these findings indicate that oxidative stress is reduced by MR feeding in rats, but this effect cannot be explained by changes in the activity of antioxidant enzymes.
OrentreichN, MatiasJR, DeFeliceA, ZimmermanJA. Low methionine ingestion by rats extends life span. J Nutr1993;123:269–74
2.
RichieJPJr, LeutzingerY, ParthasarathyS, MalloyV, OrentreichN, ZimmermanJA. Methionine restriction increases blood glutathione and longevity in F344 rats. FASEB J1994;8:1302–7
3.
MillerRA, BuehnerG, ChangY, HarperJM, SiglerR, Smith-WheelockM. Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance. Aging Cell2005;4:119–25
4.
ZimmermanJA, MalloyV, KrajcikR, OrentreichN. Nutritional control of aging. Exp Gerontol2003;38:47–52
5.
MalloyVL, KrajcikRA, BaileySJ, HristopoulosG, PlummerJD, OrentreichN. Methionine restriction decreases visceral fat mass and preserves insulin action in aging male Fischer 344 rats independent of energy restriction. Aging Cell2006;5:305–14
SunL, Sadighi AkhaAA, MillerRA, HarperJM. Life-span extension in mice by preweaning food restriction and by methionine restriction in middle age. J Gerontol A Biol Sci Med Sci2009;64:711–22
8.
SohalRS, WeindruchR. Oxidative stress, caloric restriction, and aging. Science1996;273:59–63
9.
HasekBE, StewartLK, HenaganTM, BoudreauA, LenardNR, BlackC, ShinJ, HuypensP, MalloyVL, PlaisanceEP, KrajcikRA, OrentreichN, GettysTW. Dietary methionine restriction enhances metabolic flexibility and increases uncoupled respiration in both fed and fasted states. Am J Physiol Regul Integr Comp Physiol2010;299:R728–39
10.
PlaisanceEP, HenaganTM, EchlinH, BoudreauA, HillKL, LenardNR, HasekBE, OrentreichN, GettysTW. Role of beta-adrenergic receptors in the hyperphagic and hypermetabolic responses to dietary methionine restriction. Am J Physiol Regul Integr Comp Physiol2010;299:R740–50
11.
PerroneCE, MattocksDA, Jarvis-MorarM, PlummerJD, OrentreichN. Methionine restriction effects on mitochondrial biogenesis and aerobic capacity in white adipose tissue, liver, and skeletal muscle of F344 rats. Metabolism2010;59:1000–11
12.
CaroP, GomezJ, SanchezI, NaudiA, AyalaV, Lopez-TorresM, PamplonaR, BarjaG. Forty percent methionine restriction decreases mitochondrial oxygen radical production and leak at complex I during forward electron flow and lowers oxidative damage to proteins and mitochondrial DNA in rat kidney and brain mitochondria. Rejuvenation Res2009;12:421–34
13.
GomezJ, CaroP, SanchezI, NaudiA, JoveM, Portero-OtinM, Lopez-TorresM, PamplonaR, BarjaG. Effect of methionine dietary supplementation on mitochondrial oxygen radical generation and oxidative DNA damage in rat liver and heart. J Bioenerg Biomembr2009;41:309–21
14.
Lopez-TorresM, BarjaG. Lowered methionine ingestion as responsible for the decrease in rodent mitochondrial oxidative stress in protein and dietary restriction possible implications for humans. Biochim Biophys Acta2008;1780:1337–47
15.
Sanchez-RomanI, GomezA, GomezJ, SuarezH, SanchezC, NaudiA, AyalaV, Portero-OtinM, Lopez-TorresM, PamplonaR, BarjaG. Forty percent methionine restriction lowers DNA methylation, complex I ROS generation, and oxidative damage to mtDNA and mitochondrial proteins in rat heart. J Bioenerg Biomembr2011;43:699–708
16.
Sanchez-RomanI, GomezA, PerezI, SanchezC, SuarezH, NaudiA, JoveM, Lopez-TorresM, PamplonaR, BarjaG. Effects of aging and methionine restriction applied at old age on ROS generation and oxidative damage in rat liver mitochondria. Biogerontology2012;13:399–411
17.
KomninouD, MalloyV, KrajcikR, RivensonA, OrentreichN, RichieJPJr. Methionine restriction inhibits aging-related spontaneous tumorigenesis in F344 rats lung. Proc Am Assoc Ca Res2004;45:3919
18.
GomezJ, Sanchez-RomanI, GomezA, SanchezC, SuarezH, Lopez-TorresM, BarjaG. Methionine and homocysteine modulate the rate of ROS generation of isolated mitochondria in vitro. J Bioenerg Biomembr2011;43:377–86
19.
GarlickPJ. Toxicity of methionine in humans. J Nutr2006;136:1722S–5S
20.
YalcinkayaS, UnlucerciY, GirisM, OlgacV, Dogru-AbbasogluS, UysalM. Oxidative and nitrosative stress and apoptosis in the liver of rats fed on high methionine diet: protective effect of taurine. Nutrition2009;25:436–44
21.
RichieJPJr, SkowronskiL, AbrahamP, LeutzingerY. Blood glutathione concentrations in a large-scale human study. Clin Chem1996;42:64–70
22.
TietzeF. Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues. Anal Biochem1969;27:502–22
23.
PagliaDE, ValentineWN. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med1967;70:158–69
24.
SmithIK, VierhellerTL, ThorneCA. Assay of glutathione reductase in crude tissue homogenates using 5,5′-dithiobis(2-nitrobenzoic acid). Anal Biochem1988;175:408–13
25.
MuscatJE, KleinmanW, ColosimoS, MuirA, LazarusP, ParkJ, RichieJPJr. Enhanced protein glutathiolation and oxidative stress in cigarette smokers. Free Radic Biol Med2004;36:464–70
26.
KleinmanWA, KomninouD, LeutzingerY, ColosimoS, CoxJ, LangCA, RichieJPJr. Protein glutathiolation in human blood. Biochem Pharmacol2003;65:741–6
YinB, WhyattRM, PereraFP, RandallMC, CooperTB, SantellaRM. Determination of 8-hydroxydeoxyguanosine by an immunoaffinity chromatography-monoclonal antibody-based ELISA. Free Radic Biol Med1995;18:1023–32
29.
SanzA, CaroP, AyalaV, Portero-OtinM, PamplonaR, BarjaG. Methionine restriction decreases mitochondrial oxygen radical generation and leak as well as oxidative damage to mitochondrial DNA and proteins. FASEB J2006;20:1064–73
30.
CaroP, GomezJ, Lopez-TorresM, SanchezI, NaudiA, JoveM, PamplonaR, BarjaG. Forty percent and eighty percent methionine restriction decrease mitochondrial ROS generation and oxidative stress in rat liver. Biogerontology2008;9:183–96
31.
HarmanD. Role of free radicals in mutation, cancer, aging, and the maintenance of life. Radiat Res1962;16:753–63
32.
GredillaR, BarjaG. Minireview: the role of oxidative stress in relation to caloric restriction and longevity. Endocrinology2005;146:3713–7
33.
CaroP, GomezJ, SanchezI, GarciaR, Lopez-TorresM, NaudiA, Portero-OtinM, PamplonaR, BarjaG. Effect of 40% restriction of dietary amino acids (except methionine) on mitochondrial oxidative stress and biogenesis, AIF and SIRT1 in rat liver. Biogerontology2009;10:579–92
34.
ParkCM, ChoCW, RosenfeldME, SongYS. Methionine supplementation accelerates oxidative stress and nuclear factor kappaB activation in livers of C57BL/6 mice. J Med Food2008;11:667–74
35.
StadtmanER, Van RemmenH, RichardsonA, WehrNB, LevineRL. Methionine oxidation and aging. Biochim Biophys Acta2005;1703:135–40
36.
RichieJPJr, KomninouD, LeutzingerY, KleinmanW, OrentreichN, MalloyV, ZimmermanJA. Tissue glutathione and cysteine levels in methionine-restricted rats. Nutrition2004;20:800–5
37.
BrayTM, TaylorCG. Tissue glutathione, nutrition, and oxidative stress. Can J Physiol Pharmacol1993;71:746–51
38.
EpnerDE. Can dietary methionine restriction increase the effectiveness of chemotherapy in treatment of advanced cancer?J Am Coll Nutr2001;20:443S–9S
39.
McCartyMF, Barroso-ArandaJ, ContrerasF. The low-methionine content of vegan diets may make methionine restriction feasible as a life extension strategy. Med Hypotheses2009;72:125–8
40.
RayPD, HuangBW, TsujiY. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal2012;24:981–90
