Biochimica et Biophysica Acta 1777 (2008) 1249–1262,
Membrane phospholipids, lipoxidative damage and molecular
integrity: A causal role in aging and longevity
Reinald Pamplona Department of Experimental Medicine,
University of Lleida-IRBLLEIDA, Lleida 25008, Spain
cit. -->
Table 3
Effect of caloric- protein- and methionine restriction on membrane unsaturation and advanced lipoxidation end-products (ALEs) of different rat tissues
Specie Tissue DR type (%) DR duration Effect on membrane unsaturation (PI) ALEs References
Rat Liver mitochondria 8.5% CR 7 weeks #8595; #8595; [133]
Rat Liver mitochondria 25% CR 7 weeks #8595; #8595; [133]
Rat Heart mitochondria 40% CR 4 months #8595; #8595; [130]
Rat Heart mitochondria 40% CR 1 year #8595; #8595; [80]
Rat Liver mitochondria 40% CR 4–24 months #8595; #8595; [75]
Rat Liver 40% CR 6 weeks #8595; #8595; [136]
Rat Liver 40% PR 7 weeks #8595; #8595; [132]
Rat Liver mitochondria 40% MetR 7 weeks #8595; #8595; [135]
Rat Liver mitochondria 80% MetR 7 weeks #8595; #8595; [131,135]
Rat Heart mitochondria 80% MetR 7 weeks #8595; #8595; [131]
Rat Brain 80% MetR 7 weeks #8595; #8595; [134
[metR = methionine Restriction]
[96] B.P. Yu, Membrane alteration as a basis of aging and the protective effects of
calorie restriction, Mech. Ageing Dev. 126 (2005) 1003–1010.
[131]A. Sanz, P. Caro, V. Ayala, M. Portero-Otin, R. Pamplona, G. Barja, Methionine
restriction decreases mitochondrial oxygen radical generation and leak as well as
oxidative damage to mitochondrial DNA and proteins, FASEB J. 20 (2006)
1064–1073.
[134]A. Naudí, P. Caro, M. Jové, J. Gómez, J. Boada, V. Ayala, M. Portero-Otín, G. Barja, R.
Pamplona, Methionine restriction decreases endogenous oxidative molecular
damage and increases mitochondrial biogenesis and uncoupling protein 4 in rat
brain, Rejuvenation Res. 10 (2007) 473–484.
[135]P. Caro, J. Gómez, M. López-Torres, I. Sánchez, A. Naudí, M. Jove, R. Pamplona, G.
Barja, Forty percent and eighty percent methionine restriction decrease
mitochondrial ROS generation and oxidative stress in rat liver. Biogerontology.
doi:10.1007/s10522-008-9130-1.
[152]M.C. Ruiz, V. Ayala, M. Portero-Otín, J.R. Requena, G. Barja, R. Pamplona, Protein
methionine content and MDA-lysine adducts are inversely related to maximum
life span in the heart of mammals, Mech. Ageing Dev. 126 (2005) 1106–1114
segue abstract -->
“both the limited methionine content in long-lived species reported
here and the fact that protein restriction benefits may be due to a
reduction in methionine intake are findings that would
suggest a pure pro-oxidant effect for methionine. However, a
putative anti-oxidant effect cannot be discarded. Thus, it is
possible that methionine cycling can have a protective antioxidant
effect in particular individuals, or in particular critical settings
within a protein chain, such as an active site, but that ‘‘superfluous’’
methionines tend to be eliminated by natural selection in long-lived
species. Since these species do not show reduction in methionine
reductase expression or activities, we should assume that redox
cycling of the remaining methionine residues is still important.
So, it might be simply that the anti-oxidant activity is better
focused in long-lived species, leaving less to chance.”
[129]R. Pamplona, G. Barja, Mitochondrial oxidative stress, aging and caloric
restriction: the protein and methionine connection, Biochim. Biophys. Acta
1757 (2006) 496–508 segue abstract -->
“ Caloric restriction (CR) decreases aging rate and mitochondrial ROS (MitROS)
production and oxidative stress in rat postmitotic tissues. Low levels of these
parameters are also typical traits of long-lived mammals and birds. However, it is
not known what dietary components are responsible for these changes during CR.
It was recently observed that 40% protein restriction without strong CR also decreases
MitROS generation and oxidative stress. This is interesting because protein restriction
also increases maximum longevity (although to a lower extent than CR) and is a much
more practicable intervention for humans than CR. Moreover, it was recently found that
80% methionine restriction substituting it for L-glutamate in the diet also decreases
MitROS generation in rat liver. Thus, methionine restriction seems to be responsible
for the decrease in ROS production observed in caloric restriction. This is interesting
because it is known that exactly that procedure of methionine restriction also increases
maximum longevity. Moreover, recent data show that methionine levels in tissue proteins
negatively correlate with maximum longevity in mammals and birds. All these suggest
that lowering of methionine levels is involved in the control of mitochondrial oxidative
stress and vertebrate longevity by at least two different mechanisms: decreasing the
sensitivity of proteins to oxidative damage, and lowering of the rate of ROS
generation at mitochondria.”
V. Pavillard, A. Nicolaou, J.A. Double, R.M. Philips, Methionine
dependence of tumours: a biochemical strategy for optimizing paclitaxel
chemosensitivity in vitro, Biochem. Pharmacol. 71 (2006) 772–778.
D. Komninou, Y. Leutzinger, B.S. Reddy, J.P. Richie, Methionine restriction
inhibits colon carcinogenesis, Nutr. Cancer 54 (2006) 202–208.
S.M. Lynch, J.J. Strain, Increased hepatic lipid peroxidation with
methionine toxicity in the rat, Free Radic. Res. Commun. 5 (1989)
221–226.
A.M. Troen, E. Lutgens, D.E. Smith, I.H. Rosenberg, J. Selhub, The atherogenic
effect of excess methionine intake, PNAS 100 (2003) 15089–15094.
N. Mori, K. Hirayama, Long-term consumption of a methionine supplemented
diet increases iron and lipid peroxide levels in rat liver
J. Nutr. 130 (2000) 2349–2355.
D. Matthias, C.H. Becker, R. Riezler, P.H. Kindling, Homocysteine
induced arteriosclerosis-like alterations of the aorta in normotensive and
hypertensive rats following application of high doses of methionine,
Atherosclerosis 122 (1996) 201–216.
D. Fau, J. Peret, P. Hadjiliskym, Effects of ingestion of high protein or
excess methionine diets by rats for two years, J. Nutr. 118 (1988)
128–133.
M. Toborek, E. Kopieczna-Grzebienak, M. Drózdz, M. Wieczorek,
Increased lipid peroxidation as a mechanism of methionine-induced
atheriosclerosis in rabbits, Atheriosclerosis 115 (1995) 217–224.
M. Regina, V.P. Korhonen, T.K. Smith, Alakuijala, T.O. Eloranta,
Methionine toxicity in relation to hepatic accumulation of S-adenosylmethionine:
prevention by dietary stimulation of the hepatic transsulfuration
pathway, Arch. Biochem. Biophys. 300 (1993) 598–607.
A.M. Troen, E.E. French, J.F. Roberts, J. Selhub, J.M. Ordovas, L.D.
Parnell, C.Q. Lain, Lifespan modification by glucose and methionine in
Drosophila melanogaster fed a chemically defined diet, Age 29 (2007)
29–39.
A. Naudí, P. Caro, M. Jové, J. Gómez, J. Boada, V. Ayala, M. Portero-
Otín, G. Barja, R. Pamplona, Methionine restriction decreases endogenous
oxidative molecular damage and increases mitochondrial biogenesis
and uncoupling protein 4 in rat brain, Rejuvenation Res. (Jul 30 2007),
doi:10.1089/rej.2007.0538, Electronic publication ahead of print.
W. Velez-Carrasco,M.Merkel, C.O. Twiss, J.D. Smith, Dietary methionine
effects on plasma homocysteine and HDL metabolism in mice, J. Nutr.
Biochem. ( Aug. 16 in press), doi:10.1016/j.jnutbio.2007.05.005.
Richie Jr., J.P., Leutzinger, Y., Parthasarathy, S., Malloy, V., Orentreich, N.,
Zimmerman, J.A., 1994. Methionine restriction increases blood glutathione
and longevity in F344 rats. FASEB J. 8, 1302–1307.
Stadtman, E.R., Moskovitz, J., Levine, R.L., 2003. Oxidation of methionine
residues in proteins: biological consequences. Antiox. Redox Signal. 5,
577–582.
Stadtman, E.R., Van Remmen, H., Richardson, A., Wehr, N.B., Levine,
R.L., 2005.