The ratio of the two sulfur-containing amino acids, methionine (Met) and cysteine (Cys), may be a determining factor for which foods contribute to longevity and health. It is shown here that substantially more Met than Cys is consistently found in foods, such as dairy and meat products, thought to contribute to pathologies associated with the Western Diet

John Schloss

English

Nature Precedings

1 
On the Origin of Western Diet Pathologies 
John V. Schloss1 
 1Department of Pharmaceutical Sciences, College of Pharmacy, University of New 
England, Portland, ME 04103 
The ratio of the two sulfur-containing amino acids, methionine (Met) and cysteine 
(Cys), may be a determining factor for which foods contribute to longevity and 
health.  It is shown here that substantially more Met than Cys is consistently found 
in foods, such as dairy and meat products, thought to contribute to pathologies 
associated with the Western Diet.   
The milk protein casein promotes cancer in animal studies.  When casein 
comprises 20% of total dietary calories (high protein diet), it dramatically increases the 
risk of chemically- or virally-induced cancers1.  However, when casein comprises 5% of 
the diet (low protein diet), it does not have the same cancer-promoting effect.  Soy 
protein or wheat gluten does not have the same cancer-promoting effect, even when 
either one comprises 20% of the diet1.  Comparison of the amino acid compositions of 
casein, soy protein, and wheat gluten indicates that the relative amounts of Met and Cys 
are responsible for the differences in the cancer-promoting effects of high-casein and 
other diets in animals.  Casein2 contains substantially more Met and less Cys than soy2 
or wheat gluten3 (Table 1).  To account for the differences in the cancer promoting 
effects of these proteins a four-fold difference in composition or greater is expected 
(i.e., 5 vs. 20% dietary casein).  The Met/Cys ratio is the major difference in the amino 
acid compositions of casein, soy, and wheat gluten (6- to 10-fold).  The absolute 
amounts of Met (two-fold difference) or Cys (3- to 5-fold difference) alone do not 
appear to be sufficient to explain the different cancer-promoting effects.  None of the 
other amino acids that comprise these proteins differ to the same extent, nor are there 
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consistent differences between soy, gluten and casein with respect to other constituent 
amino acids.   
While suggestive, animal-feeding studies may not accurately reflect the health 
consequences of diet composition in humans.  Milk from ruminant animals4 has a much 
higher Met and lower Cys content [Met/Cys = 3-4.3] than human4 milk [Met/Cys = 
0.81].  It could be argued that the Met/Cys ratio observed in human human milk has 
been selected for optimal neonatal nutrition.  Based on epidemiological studies1, a diet 
high in animal proteins contributes to various pathologies, such as cancer, heart disease, 
diabetes, and osteoporosis.  Dairy and meat products have higher Met/Cys ratios (Fig. 
1), than legumes, grains, fruits, and vegetables5.  Diets high in animal proteins, but not 
diets high in plant proteins, have been reported to correlate with an increased risk of 
osteoporosis6.  Milk and cheese in particular have exceptionally high ratios of Met/Cys.  
While the absolute amount of Met is nearly equivalent for cheese and soy, the amount 
of Cys is 7-fold greater in soy than in cheese (Table 2).  In a 12-year prospective study, 
milk consumption not only failed to decrease the risk of hip fracture, but increased the 
fracture risk slightly (1.45-fold)7.  This observation is consistent with reports that Met-
derived homocysteine (Hcy) can adversely affect the quality of bone collagen and 
increase the risk of fracture even when adequate calcium intake maintains bone 
density8.   
Met and Cys are inextricably linked by the transsulfuration metabolic pathway 
(Fig. 2).  Met can be converted to Cys via the transsulfuration pathway, but Cys cannot 
be converted to Met.  Dietary studies have focused primarily on Met and Met-derived 
Hcy.  The absolute amounts of dietary Met and Met-derived Hcy have been linked to 
lifespan and age-related pathologies.  Met restriction extends lifespan in Drosophila and 
rodents without caloric restriction9.  Met restriction selectively blocks cancer 
proliferation in humans10-11.  Met-derived Hcy promotes atherosclerosis12.  Hcy is also 
3 
implicated in cancer13, diabetic neuropathy14, open-angle glaucoma15, and 
osteoporosis16.   
The pathologies associated with the transsulfuration pathway are likely to be 
mediated in part through a common mechanism.  Hcy and its oxidation products 
activate glutamate receptors, which are tied to pathologies of the central nervous 
system17.  Glutamate receptors are also present in other cell types, such as pancreatic 
islet cells, kidney, heart, bone, lymphocyte, and skin cells18.  The wide distribution of 
glutamate receptors offers a potential explanation for the diverse pathologies associated 
with transsulfuration pathway dysfunction.  The most common reason for inherited 
homocystinuria is a deficiency in the enzyme responsible for converting Hcy to 
cystathionine (Fig. 2)12.  Deficiencies of the transsulfuration enzymes (Fig. 2) or 
nutritional deficiencies for the necessary cofactors (folic acid, B6, or B12) can lead to 
hyperhomocysteinemia and resultant pathologies.  Depending on the relative amounts of 
Met and Cys in the diet, elevated Hcy can also be associated with depressed levels of 
Cys and Cys-dependent products, in particular glutathione and taurine.  Glutathione and 
Hcy would have competing effects on glutamate receptors, such that depression of Cys 
would exacerbate the pathologies associated with hyperhomocysteinemia (Fig. 2).   
If Met-derived Hcy is responsible for age-related diseases, then dietary Cys 
supplementation should offset disease progression.  Dietary Cys, provided as N-acetyl 
cysteine (NAC), can lower blood levels of Hcy19.  NAC has been reported to increase 
HDL-cholesterol20; improve insulin sensitivity in patients with polycystic ovary 
syndrome21; reduce the risk of cancer22; reduce atherosclerosis in apolipoprotein E-
deficient mice23; increase immune function in HIV+ patients24, and slow bone resorption 
in post-menopausal women25.  When examining the relationship between various 
pathologies and diet, the effects of NAC supplementation suggest that the ratio of Met 
and Cys be given special attention, rather than considering absolute amounts of each 
4 
alone.  Balancing the relative amounts of the two sulfur-containing amino acids in the 
diet may help to prevent age-related diseases.   
1. Campbell, T. C. Dietary protein, growth factors, and cancer. Am. J. Clin. Nutr. 
85, 1667 (2007). 
2. Rutherfurd, S. M. & Moughan P. J. The digestible amino acid composition of 
several milk proteins: application of a new bioassay. J. Dairy Sci. 81, 909-917 
(1998). 
3. Rombouts, I. et al. Wheat gluten amino acid composition analysis by high-
performance anion-exchange chromatography with integrated pulsed 
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124, 1126-1132 (1994).  
5. FAO, A report of FAO/UN Joint Committee: Rome, Italy, P-84 (1981).  
6. Feskanich, D., Willett, W. C., Stampfer, M. J. & Colditz, G. A. Protein 
consumption and bone fractures in women. Am. J. Epidemiol. 143, 472-479 
(1996).  
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959-964 (2009).  
9. Grandison, R. C., Piper, M. D. & Partridge, L. Amino-acid imbalance explains 
lifespan by dietary restriction in Drosophila. Nature 462, 1061-1064 (2009).  
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10. Durando, X. et al. Dietary methionine restriction with FOLFOX regimen as first 
line therapy of metastatic colorectal cancer: a feasibility study. Oncology 78, 
205-209 (2010).  
11. Epner, D. E. Can dietary methionine restriction increase the effectiveness of 
chemotherapy in treatment of advanced cancer? J. Am. Col. Nutr. 20, 443S-449S 
(2001).  
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13. Ferroni, P. et al. Determinants of homocysteine levels in colorectal and breast 
cancer patients. Anticancer Res. 29, 4131-4138 (2009).  
14. Wile, D. J. & Toth, C. Association of metformin, elevated homocysteine, and 
methylmalonic acid levels and clinically worsened diabetic peripheral 
neuropathy. Diabetes Care 33, 156-161 (2010).  
15. Clement, C. I., Goldberg, I., Healey, P. R. & Graham, S. L. Plasma 
homocysteine, MTHFR gene mutation, and open-angle glaucoma. J. Glaucoma 
18, 73-78 (2009).  
16. Petramala, L., Acca, M., Francucci, C. M. & D’Erasmo, E. 
Hyperhomocysteinemia: a biochemical link between bone and cardiovascular 
system diseases? J. Endrocrinol. Invest. 32, 10-14 (2009).  
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derivatives are potent and selective metabotropic glutamate receptor agonists. J. 
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methyl-D-aspartate receptors functionally active in controlling T cell activation. 
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6 
19. Wiklund, O. et al. N-acetylcysteine treatment lowers plasma homocysteine but 
not serum lipoprotein(a) levels. Atherosclerosis 119, 99-106 (1996).  
20. Franceschini, G., Werba, J. P., Safa, O., Gikalov, I. & Sirtori, C. R. Dose-related 
increase of HDL-cholesterol levels after N-acetylcysteine in man. Pharmacol. 
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restores gonadal function in patients with polycystic ovary syndrome. J. 
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22. Millea, P. J. N-acetylcysteine: multiple clinical applications. Am. Fam. 
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apolipoprotein E-deficient mice by reducing superoxide production. Circ. J. 73, 
1337-1341 (2009).  
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sulfur supplementation: two randomized trials. J. Mol. Med. 78, 55-62 (2000). 
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menopausal women: a pilot study. Transl. Res. 150, 215 (2007).  
 
 
 
 
 
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________________________________________________________ 
Table 1 | Comparison of casein, soy, and gluten 
________________________________________________________ 
 
    Met    Cys    Met/Cys 
                                 _________________________ 
        (mg/g protein) 
 
Casein2   28.5      3.7        7.7 
Soy2    12.6    10.5        1.2 
Gluten3  13.1   17.5       0.75 
------------------------------------------------------------------------------------------------ 
 
1 
________________________________________________________ 
Table 2 | Comparison of various foods 
________________________________________________________ 
 
    Met    Cys    Met/Cys 
                                 _________________________ 
               (mg/100 g food)5 
 
Milk      86      28        3.1 
Cheese   530      76        7.0 
Beef    478    226        2.1 
Chicken   502    262        1.9 
Lamb    383    200        1.9 
Pork    321    133        2.4 
Fish    539    220        2.4 
Wheat    196    332        0.59 
Corn    182    147        1.2 
Oats    234    372        0.63 
Rye    172    225        0.76 
Broad bean   172    187        0.92 
Chickpea   209    238        0.88 
Soybean   525    552        0.95 
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On the Origin of Western Diet Pathologies

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On the Origin of Western Diet Pathologies

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